SE500216C2 - 1-Sulpho-3-amino-2-oxo-azetidine salt derivs. - useful as antibacterials for human or veterinary use - Google Patents

Abstract

Beta lactams (I) having an SO3M substit. at 1-position and an opt. substd. or protected amino gp. or azido gp. at the 3-position are new. (M is hydrogen or a cation). They can also be substd. at the 4-position by alkyl, cycloalkyl, opt. substd. phenyl, alkoxycarbonyl, alken-1-yl, alkyn-1-yl, 2-phenylethenyl or 2-phenylethynyl. (I) having a 3-acylamino substit. are antibacterials effective against Gram negative and positive species, and useful therapeutically in human or veterinary medicine. The other new cpds. are intermediates.

Description

500 216 2 Ia y É2 É fl NH2-T í-R3 C N-sogmæ o? 3 These compounds are intermediates useful for the preparation of the corresponding 3-acylamino compounds.

As used in formulas I and Ia and in the description below, the symbols used have the following meanings: R 1 is acyl; R 2 R 3 and R 4 are the same or different and each represents hydrogen, alkyl, cycloalkyl, phenyl or substituted phenyl, or one is hydrogen or alkoxy having 1-4 carbon atoms; of R 3 and R 4 hydrogen and the other alkoxycarbonyl, alken-1-yl, alkyn-1-yl, 2-phenylethenyl or 2-phenylethynyl. g Mæ is hydrogen or a cation.

The terms "alkyl" and "alkoxy" refer to both straight and branched chain groups. The groups having 1-10 carbon atoms are preferred.

The terms "cycloalkyl" and "cycloalkenyl" refer to cycloalkyl and cycloalkenyl groups containing 3, 4, 5, 6 or 7 carbon atoms.

The term "alkenyl" refers to both straight and branched chain groups. The groups having 2-10 carbon atoms are preferred.

The term "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl and lower alkyl or alkoxy groups.

The term "protected carboxyl" refers to a carboxyl group esterified with a conventional ester protecting group. These groups are well known in the art; compare, for example, U.S. Patent 4,144,333. The preferred protected carboxyl groups are benzyl, benzhydryl and t-butyl esters.

The term "acyl" embraces all organic groups derived from an organic acid (ie, a carboxylic acid) by removal of the hydroxyl group. Some acyl groups are of course preferred, but this preference should not be construed as limiting the scope of the invention. on acyl groups are those acyl groups previously used for acylation of β-1-lactam antibiotics, including 6-aminopenicillanic acid and derivatives thereof and 7-aminocephalosporanic acid and derivatives thereof; compare, for example, Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972), DOS 2,716,677, published October 10, 1978, Belgian Patent 867,994, published December 11, 1978, U.S. Patents 4,152,432, 3,971,778, 4,172,199 and British Patent Specification 1,348,894. The portions of these references, describing various acyl groups, is hereby incorporated by reference. The following list of acyl groups is given to further exemplify the term "acyl"; it is not intended to limit the meaning of the term. Examples of acyl groups are the following: (a) Aliphatic groups of the formula o R 5 -c- wherein R 5 is alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; cyclohexadienyl; or alkyl- or alkenyl-substituted with one or more groups of halogen, cyano, nitro, amino, mercapto, alkylthio or cyanomethylthio. (b) Carbocyclic aromatic groups of the formula 500 216 4 Rv o R3 H (CH2) n-C-, R _. 7 O R Rg H cH-C-, __ 1 Rs R7 O Rs 8 "'o-cnz-c-.

R 7 is Re R u S_CH 2_C_ or R 7 wherein n is 0, 1, 2 or 3; R 6, R 7 and R 8 each independently represent hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or aminomethyl; and R 9 represents amino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfosalt, a sulfoaminosalt, azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino or [(alkylthio) thioxomethyl] thio. Preferred carbocyclic aromatic acyl groups include those having the formula II '(R 9 is preferably a carboxyl salt or a sulfosalt) and O H <::>} - CH-C- (R 9 is preferably 1 R 5 is a carboxyl salt or a sulfosalt). (c) Heteroaromatic groups of the formula O u) -C-, R 10 - (CH n R 10 öf- "'Ra" If 500 216 yari n is 0, 1, 2 or 3; R 9 is as defined above; and R 10 is a substituted or unsubstituted 5-, 6- or 7-atom heterocyclic ring containing 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms Examples of heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyly pyrazinyl , thiazolyl, morpholinyl, pyrimidinyl and tetrazolyl.

Examples of substituents are halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms or alkoxy of 1-4 carbon atoms.

Preferred heteroaromatic acyl groups include those groups of the above formulas wherein R 10 is 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1,2,4 -thiadiazol--5-yl, 2-thienyl or 2-furanyl. (d) [[(4-Substituted 2,3-dioxo-1-piperazinyl) carbonyl] amino] arylacetyl groups of the formula O O / Ä I -H N | -c-CH-NH-c-N in Ru A O O 'Ru wherein R is an aromatic group (including carbocyclic II aromatics such as those having the formula and heteroaromatics included within the definition of R 10); and R 12 is alkyl, substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups), arylmethylenamino (ie -N = CH-R 11 wherein R is as defined above) , arylcarbonylamino (i.e. 11 O -NH-ER 1, wherein R 11 has the meaning given above) or alkyl-1 500 216 'Vcarbonylamino.

Preferred [[(4-substituted 2,3-dioxo-1-piperazinyl) carbonyl] amino] -arylacetyl groups include those wherein R 12 is ethyl, phenylmethylenamino or 2-furylmethylenamino. (e) (Substituted oxyimino) arylacetyl groups having the formula wherein R 11 is as defined above and R 13 is hydrogen, alkyl, cycloalkyl, alkylaminocarbonyl, arylaminocarbonyl (i.e.

O -C-NH-R 11, wherein R 11 is phenyl, optionally substituted with nitro and tetrazole) or substituted alkyl [wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio , aromatic groups (as defined for R11), carboxyl (including salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinylphosphyl substituents].

Preferred (substituted oxyimino) arylacetyl groups include those wherein R 11 is 2-amino-4-thiazolyl. Also preferred are those groups in which R 13 is methyl, ethyl, carboxymethyl or 2-carboxyisopropyl. (f) (Acylamino) arylacetyl groups of the formula O 0 u u ll -C 1 -H-NH-C-R 14 R 11 wherein R 11 is as defined above and R 14 is 500 216 Rv R R 8) -O-. .

(CH 2 n, amino, alkylamino, (cyanoalkyl) -amino, amido, alkylamido, (cyanoalkyl) -amido, Ng NH O .g I 2 u -C52-NH-C - <â :: š _, -CH- CH2-C-NH-CH3 1 H / \ soz-bucuz-cuz-oxnz, / \ G43, __N .N on _ OH OH N, / šN o / / \ / \ ui or Û f N N-cu \ N Preferred (acylamino) arylacetyl groups of the above formula include those in which R 14 is amino or amido, and also preferred are those in which R 11 is phenyl or 2-thienyl. (9) [ [[3-Substituted 2-oxo-1-imidazolidinyl] carbonyl] amino] arylacetyl groups of the formula 500 216 wherein R 11 is as defined above and R 11 is hydrogen, alkylsulfonyl, arylmethylenamino (ie -N = CH-R 11 , wherein R 11 is as defined above), -α-R (wherein R is hydrogen, alkyl or halogen-substituted alkyl), an aromatic group (as defined for R 11 above), alkyl or substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups).

Preferred [[3-substituted 2-oxo-1-imidazolidinyl] carbonyl] amino] arylacetyl groups of the above formula include those wherein R 11 is phenyl or 2-thienyl. Also preferred are those groups wherein R 15 is hydrogen, methylsulfonyl, phenylmethylenamino or 2-furylmethylenamino.

The term "cation" as used herein refers to any positively charged atom or group of atoms. The substituent -SOÉMQ at the nitrogen atom of the β-lactams according to the invention comprises all sulfonic acid salts. Pharmaceutically acceptable salts are of course preferred although other salts are also useful for purifying the products of the invention or as intermediates for the preparation of the pharmaceutically acceptable salts. The cationic portion of the sulfonic acid salts of the invention can be obtained either from organic or from inorganic bases. Such cationic moieties include, but are not limited to, the following ions: ammonium; substituted ammonium, such as alkylammonium (eg tetra-n-butylammonium, hereinafter referred to as tetrabutylamonium); alkali metal such as lithium, sodium and potassium; alkaline earth metals such as calcium and magnesium; pyridinium; dicyclohexylammonium, hydrabaminium; benzatinium; N-methyl-D-glucaminium.

As stated in formula I and in the definitions following formula I, Mæ may be hydrogen.

As described below, the β-lactams of the invention can be prepared synthetically. The non-alkoxylated 4-unsubstituted β-lactams of formula I, i.e. The compounds of formula I in which R 1 and R 4 are hydrogen can be prepared using 6-acinosenicillanic acid or a 6-acylaminopenicillanic acid as starting material. The β-lactams of formula I, wherein R 2 is alkoxy, can be prepared from the corresponding non-alkoxylated β-lactam. Certain compounds of the invention may be crystallized or recrystallized from solvents containing water. In these cases, hydration water can be formed.

The invention includes stoichiometric hydrates as well as compounds containing varying amounts of water which can be formed by methods such as lyophilization.

Some β-lactams of formula I have also been biologically produced.

Culture of a strain of the microorganism Chromobacterium violaceum SC 11,378 gives a salt of (R) -3- (acetylamino) -3-methoxy-2-oxo-1-azetidinesulfonic acid.-Culture of various acetic acid bacteria, e.g. Gluconobacter species SC ll.435, gives a salt of (R) -3 - - [[N- (D-T-glutamyl) -D-alanyl] amino] -3-methoxy-2-oxo-1-azetidinesulfonic acid.

Β-lactams with a sulfonic acid salt substituent 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 in the β-lactam nucleus) to which the amino- or acylamino substituent is attached. The invention also relates to the β-lactams described above, wherein the stereochemical configuration at the chiral center in the 3-position in the β-lactam nucleus is the same as the configuration at the carbon atom in the 6-position of naturally occurring penicillins (eg penicillin G) and as the configuration at the carbon atom in the 7-position in naturally occurring cephamycins (eg cephamycin C).

With respect to the preferred β-lactams of formulas I and Ia, the structural formulas have been designed to show the stereochemical configuration at the chiral center in the 3-position.

Due to the nomenclature convention, the compounds of formulas I and Ia, wherein R 2 is hydrogen, have the S-configuration and the compounds of the formulas I and Ia, wherein R 2 is alkoxy, have the R-configuration. The invention also encompasses racemic mixtures containing the β-lactams described above.

Β-lactams with a sulfonic acid salt substituent in the 1-position in the β-lactam nucleus and an amino- or acylamino substituent in the 3-position in the β-lactam nucleus show activity against a variety of gram-negative and gram-positive organisms. The sulfonic acid-salt substituent is essential for the activity of the compounds according to the invention. The compounds in which R 3 and / or R 4 are hydrogen or alkyl, especially methyl, show a particularly useful activity.

The compounds of the invention may be used as agents for combating bacterial infections (including urinary tract and respiratory tract infections) in mammalian species, e.g. domestic animals (eg dogs, cats, cows, horses and the like) and humans.

To control bacterial infections in mammals, a compound of the invention may be administered to the 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 methods of administration previously used for the administration of penicillins and cephalosporins to the site of infection are also intended to be used for the new family of β-lactams according to the invention. Such delivery methods include oral, intravenous, intramuscular delivery and in the form of a suppository.

The β-lactam products of the invention are generally prepared by introducing a sulfonic acid substituent (a sulfo group -SO 3 -) onto the nitrogen atom at the 1-position in the β-lactam nucleus.

This sulfonation reaction is readily carried out by treating the β-lactam with a sulfur trioxide complex or with an equivalent sulfonating agent, such as a chlorosulfonate.

The most commonly used sulfur trioxide complexes are pyridine-sulfur trioxide; lutidine-sulfur trioxide, dimethylformamide-sulfur trioxide; and picoline-sulfur trioxide. Instead of using a pre-formed complex, the complex can be formed in situ, e.g. using chlorosulfonyl-trimethylsilyl ester and pyridine as reagents. Alternatively, the sulfonation can be accomplished by an intermediate compound such as, for example, first silylating the nitrogen atom in the β-lactam nucleus and then subjecting the silated compound to a silyl exchange reaction with trimethylsilyl chlorosulfonate or a similar reagent. Examples of silylating agents are monosilyl trifluoroacetamide, trimethylsilyl chloride / triethylamine and bis-trimethylsilyl trifluoroacetamide.

In general, the sulfonation reaction is carried out in the presence of an organic solvent such as pyridine or a mixture of organic solvents, preferably a mixture of a polar solvent such as dimethylformamide and a halogenated hydrocarbon such as dichloromethane.

The product initially formed in the sulfonation reaction is a salt of the sulfonated β-lactam. When pyridine-sulfur trioxide is the sulfonating complex, the initially formed product is the β-lactam sulphonated pyridinium salt of the sulphonated β-lactam, wherein M + in the formula number is pyridinium- I - + ---- -so M in the ion: These complexes can be converted to other sulfonic acid salts using conventional techniques (eg, ion exchange resins, crystallization or ion pair extraction). These conversion methods are also useful for purifying the products.

Conversion of the pyridine salt to the potassium salt using potassium phosphate or potassium ethyl hexanoate; to the tetrabutylammonium salt using tetrabutylammonium hydrogen sulfate; or to a zwitterionic compound (M + = hydrogen) using formic acid; is particularly useful. It should be understood that the sulfonation reaction which introduces the sulfo group on the nitrogen atom of the β-lactam nucleus can be carried out at various stages of the synthesis, including introduction before the formation of the β-lactam nucleus, such a process being carried out as indicated below. The sulfonation reaction is carried out in the presence of the solvents described above and usually at room temperature. When the amino function is present, the reaction is preferably carried out with the amino function protected.

Using a benzyloxycarbonyl protecting group as an example, the sulfonation reaction can be illustrated in the following manner: z 4 Rz 1124 q conco zo-NH R 3 HZN-3 --- ~%> - +. N-SO M /,: NH l) sulfonation Q ”3 II 2) deprotection III Other protecting groups can be used to protect the amino function, e.g. a t-butyloxycarbonyl group, a simple acyl group such as acetyl or benzoyl of phenylacetyl, a triphenylmethyl group, or having the amino function in the form of an azide group. The desired acyl group 1 (R 1) can be attached in a conventional acylation reaction.

Examples of acylation processes for the conversion of a compound of formula III to a product of formula I include reaction with a carboxylic acid (R 1 -OH) or the corresponding carboxylic acid halide or carboxylic anhydride. When R 2 is alkoxy, acylation is best accomplished using an acid chloride or an acid bromide. The reaction with a carboxylic acid proceeds most easily in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance which can form an active ester in situ such as N-hydroxybenzotriazole. In cases where the acyl group (R1) contains reactive functions (such as amino or carboxyl groups) it may be necessary to first protect these functional groups and then carry out the acylation reaction and finally deprotect the resulting product. Alternatively, the sulfonation reaction can be carried out with the acyl group already in position, for example: R z "4 R2 34 R -Nu- _ = RR -NH- = R 1 3 š i I 3 '- + ø H sulfonation Å H_SO3M Q In the case where R 2 is lower alkoxy, further variation may be present since the R 2 lower alkoxy group may be introduced after the sulfonation as well as before the sulfonation using conventional procedures for chlorination of the acylated nitrogen atom in the 3-position followed by reaction with a lower alkoxide '4 (R2) alkoxide R2 lll' JU 4 _ - + -So 14+ -SO3M 4 Q w VI V The acyl groups in the above reaction scheme also include readily removable groups which act as a protecting group and which can be removed after the reaction to obtain of the "deacylated" product (-NH 2).

In addition, the β-lactam ring can be formed via a cyclization reaction and the sulfonation reaction can be carried out before the cyclization as well as thereafter, i.e. The ACyl group in this reaction can also be an easy removal......................................... bare group, which functions as a protecting group and which, after removal, gives the NH2 product.

The azetidinone starting materials, wherein R 2 is hydrogen and at least one of R 3 and R 4 is hydrogen, can also be prepared from amino acids having the formula R NH OH 4 2 \ å xII Gli -__ '\ \ RB OH o // C (at least one of R 3 and R 4 are hydrogen). The amino group is first protected with a classical protecting group, e.g. t-butoxycarbonyl (hereinafter referred to as "Boc"). The carboxyl group of the protected amino acid is then purified to react with an amine salt having the formula XIII Yo-Nnscl 'wherein Y is alkyl or benzyl, in the presence of a carbodiimide to give a compound having the formula XIV soc-NH-cH-- o / ”C 500 216 16 (at least one of R3 and R4 is hydrogen). The hydroxyl group of a compound of formula XIV is converted into a leaving group (V) with a classical reagent, e.g. methanesulfonyl chloride (methanesulfonyl is hereinafter referred to as "Ms"). Other leaving groups (V) that can be used are benzenesulfonyl, toluenesulfonyl, chlorine, bromine and iodine.

The fully protected compound having the formula BOC-NH-TH --- C C O? (mint one of R 1 and R 4 is hydrogen) is cyclized by treatment 3 with a base, e.g. potassium carbonate. The reaction is preferably carried out in an organic solvent such as acetone under reflux conditions to give a compound having the formula BOC-NH R3 XVI ß | (at least one of R 3 and R 4 is hydrogen).

Alternatively, the cyclization of a compound of formula XIV can be accomplished without first converting the hydroxyl group to a leaving group. Treatment of a compound of formula XIV with triphenylphosphine and diethyl azodicarboxylate gives a compound of formula XVI, wherein at least one of R 3 and R 3 is hydrogen.

Removal of the protecting group from the 1-position of an azetidinone of formula XVI can be performed via sodium reduction when Y is alkyl to give an intermediate of formula XVII (at least one of R 3 and R 4 is hydrogen). If Y is benzyl, catalytic (eg palladium on carbon) hydrogenation initially gives the corresponding N-hydroxy compound, which after treatment with titanium trichloride gives an intermediate of formula XVII, wherein at least one of R 3 and R 4 is hydrogen.

Synthesis involving cyclization of the type described above results in an inversion of the stereochemical configuration of the substituents R3 and R4.

As mentioned above, the above-mentioned azetidinone can be sulfonated to give a compound having the formula 134 xvnx 10Boc-NH- = (at least one of R 3 and R 4 is hydrogen).

An alternative process for the preparation of a compound of formula I, wherein R 2 is hydrogen and at least one of R 1 and R 2 is hydrogen, uses as starting material an amino acid amide of the formula OH R 1/2 NH 2 -T 2 ; NH 2 (at least one of R 3 and R 4 is hydrogen).

Protection of the amino group with a classic protecting group, e.g. benzyloxycarbonyl (hereinafter referred to as "Z") or Boc and conversion of the hydroxyl group to a leaving group (V) such as Ms gives a compound having the formula OMs R xx / 4 ANH-CH --NH 2 3 (at least one of R 3 and R 4 is hydrogen), wherein A is a protecting group.

Sulfonation of a compound of formula XX gives a compound having the formula ANH-cH --- c xx1 | R 1 + O 5 C NHSO 3 M (at least one of R 3 and R 4 is hydrogen).

Cyclization of a compound of formula XXI is performed with a base, e.g. potassium carbonate. The reaction is preferably carried out in a mixture of water and an organic solvent, e.g. a halogenated hydrocarbon such as 1,2-dichloroethane) under reflux conditions to give a compound having the formula XXII (at least one of R 3 and R 4 is hydrogen).

Deprotection of a sulfonated azetidinone of formula XXII, wherein A is a protecting group, as well as corresponding compounds as described above having an R 2 alkoxy group by catalytic hydrogenation gives a compound having the formula 500 21è 19 Rz R 4 HZN - 113 xxrrx - + N -so M 0/3 (at least one of R 3 and R 4 is hydrogen), wherein R 2 is hydrogen or alkoxy, which can be converted to the corresponding zwitterion of the formula R Rz -4 + _ = R xxIv m3 I 3 O¿ _-- N -so 3 (at least one of R 3 and R 4 is hydrogen) by treatment with an acid such as formic acid.

Deprotection of a sulfonated azetidinone of formula XXII, wherein A is a Boc protecting group, using acidic conditions (eg using formic acid) gives the corresponding zwitterion of formula XIV.

An excellent source of the β-lactam starting materials are the 6-aminopenicillanic acids and the 7-aminocephalosporanic acids, which may exhibit any 6-alkoxy- or 7-alkoxy substituent.

These compounds have the formulas Rz / CH3 R1-NH--\ KI * \ CH3 xxva, / -_-- N c-cooH o resp. 5OÛ 216 2o A R. ß s R -NH _- * - * T // xxvb 1 year N /, cH3 o coon wherein R 2 is hydrogen or alkoxy and R 1 is hydrogen or acyl.

By adapting procedures described in the literature, 3-amino-2-azetidinones can be prepared; compare, for example, Chem. Soc. Special Publication no. 28, pp. 288 (1977); The Chemistry of Penicillins, Princeton University Press, p. 257 and Synthesis, 494 (1977). The 6-amino-penicillanic acid or 7-aminocephalosporanic acid is first desulfurized by reduction using Raney nickel.

The reaction can be carried out in water under reflux conditions; the resulting compound has the structural formula xxxvi N-cu-cH (cH3) 2 COOH Replacement of the carboxyl group of the compound of formula XXVI with an acetate group followed by hydrolysis gives a 3-amino-3-alkoxy-2-azetidinone of formula I, wherein R1 is hydrogen or acyl, R 2 is hydrogen or lower alkoxy and R 3 and R 4 are hydrogen. Treatment of a compound of formula XXVI with cupric acetate and lead tetraacetate in an organic solvent (eg acetonitrile) replaces the carboxyl group with an acetate group. Hydrolysis of the formed compound can be performed using potassium carbonate in the presence of sodium borohydride.

Introduction of a sulfo group in the 1-position of a compound 3-amino-3-alkoxy-2-azetidinone can be accomplished by reacting the intermediate with a complex of dimethylformamide and sulfur son 216 "21 trioxide.

A 3-azido-2-azetidinone starting material can be prepared by first reacting an olefin of the formula R t4 XXVII CflzC-RB with a halosulfonyl isocyanate (preferably chlorosulfonyl isocyanate) of the formula xxv1II 2 to form an azetidone of R R3 XXIX N-soz-halo fl / O / Reductive hydrolysis of an azetidinone of formula XXIX gives an N-unsubstituted β-lactam of formula R3 XXX For a more detailed description of the above reaction sequence, reference is made to the literature; compare, for example, Chem. Soc. Rev., ä, 181 (1976) and J. Org. Chem., 35, 2043 (1970).

An azido group can be introduced into the 3-position of an azetidinone of formula XXX (or its sulfonated equivalent) by reacting the compound with an arylsulfonyl azide (such as toluenesulfonyl azide) to give a starting azetidinone of the formula 500 216 22 N37 R3 XXXI 1 of The reaction proceeds best by first protecting the acetidinone nitrogen with a silyl residue (eg t-butyldimethylsilyl or t-butyldiphenylsilyll), after which the anion is generated at the 3-position of the nucleus with a strong organic base (eg lithium di isopropylamine) at low temperature with subsequent treatment of the anion with toluenesulfonyl azide The intermediate formed is treated with trimethylsilyl chloride and subsequent acid hydrolysis or fluoride solvolysis of the N-protecting group gives the compound of formula XXXI.

Alternatively, the compound of formula XXXI can be obtained by first reacting a primary amine having the formula H N-CH O-alkyl-1 in 2Q 'or HZNQQ aiky-O-alkyl with an aldehyde having the formula R3CH = O to formation of the corresponding Schiff base. A [2 + 2] -cyclodition with an activated form of -azidoacetic acid gives a 3-azido-2-azetidinone of the formula R4 N-R3 / f-Nr fi 2 o-alkyl GO-alkyl or wherein Q is -CHO -alkyl 500 216 '23 Oxidative removal of the Q substituent gives the compound of formula XXXI. The 3-acylamino-2-azetidinones can be obtained by first reducing a 3-azido-2-azetidinone of formula XXXI to give the corresponding 3-amino-2-azetidinone, then acerylating the 3-amino-2-azetidinone.

When R 2 is lower alkoxy, as mentioned above, the product can be prepared from the corresponding product, wherein R 2 is hydrogen. Chlorination of the amide nitrogen in a non-alkoxylated compound gives an intermediate of the formula beer 4 B4 _ _ = R _ R1 N 3 XXXII - + G4 N-SO 3 M Reagents and processes for N-chlorination of amides are well known. Examples of reagents are tert-butyl hypochlorite, sodium hypochlorite and chlorine. The reaction can be carried out in an organic solvent (eg a lower alkanol such as methanol) or in a two phase solvent system (eg water / methylene chloride) in the presence of a base such as sodium borate decahydrate. The reaction is preferably carried out at reduced temperature.

Reaction of an intermediate having the formula XXXI with an alkoxylating agent, e.g. an alkali metal alkoxide, gives a product of formula I, wherein R 2 is alkoxy, in combination with its enantiomer. The reaction can be carried out in an organic solvent, e.g. a polar organic solvent, such as dimethylformamide, at reduced temperature.

An alternative synthesis for the preparation of the compounds of formula I, wherein R 2 is alkoxy, first comprises alkoxylation of an intermediate of formula VI, wherein RINH is a carbamate (eg R 1 is benzyloxycarbonyl) and R 2 is hydrogen, sulfo group in the 1-position of the obtained compound. Chlorination of a compound of formula VI using the procedure described above for chlorination of a non-alkoxylated compound of formula I to give a compound of formula XXXII gives an intermediate having the formula I {XxIII C6H5-CH2- Using the alkoxylation procedure described above (for converting a compound of formula XXXII to a product of formula I) and subsequently adding a reducing agent. agents such as trimethylphosphite, the compound of formula XXXIII may be converted into an intermediate of the formula O-alkyl R c H o-co-NH-3 R xxxIv 6 5 I 3 in combination with its enantiomer.

The processes described above give the products of formula I, wherein R 2 is alkoxy, as a racemic mixture. If desired, the enantiomer of configuration R can be isolated from the racemic mixture using conventional methods such as fractional crystallization of an appropriate salt with an optically active organic amine or by ion-paired chromatography using an optically active cation. Biological preparation of antibiotic EM5117 Salts of (R) -3- (acetylamino) -3-methoxy-2-oxo-1-azetidinesulfonic acid (formula I, R1 of acetyl and R2 is methoxy; hereinafter referred to as EM5117). ) can also be prepared by culturing a strain of the microorganism Chromobacterium violaceum SC 11,378 deposited in the American Type Culture Collection as ATCC no. 31532.

The microorganism- The microorganism used to produce EM5117 is a strain of Chromobacterium violaceum SC 11,378. A subculture of the microorganism can be obtained from the permanent collection of the American Type Culture Collection, Rockville, Maryland, USA. Its availability number in the depository is ATCC no. 31532. In addition to the specific micro-organism described and characterized below, it should be understood that mutants of the micro-organism (eg mutants produced using X-rays, ultraviolet radiation or mustard gas) can also be cultured to form EM5117.

Chromobacterium violaceum SC 11,378, ATCC no. 31532 can be isolated from a moist soil sample containing the microorganism by first depositing the soil sample on a medium containing: soil extract 400 ml distilled water 600 ml yeast extract 5.0 g glucose l0.0 g agar 17.5 g The medium is adjusted to pH 6.0 and sterilized in an autoclave at 120 ° C for 20 minutes. After 24-72 hours of incubation at 2500, colonies of Chromobacterium violaceum SC ll.378 are isolated from the soil on the plate. These isolated colonies are then grown on a medium containing: 500 216 26 yeast extract g meat extract g "NZ amine A" g glucose 10 g agar 15 g distilled water to 1 liter The medium is adjusted to pH 7.3 and autoclaved at 112 ° C in 30 minutes.

Chromobacterium violaceum SC ll.378 is a gram-negative rod that often shows branching, bipolar staining and lipid inclusions. It is motile due to a single polar flagellum with temporary lateral flagella, which is smaller in size.

On nutrient agar, Chromobacterium violaceum SC ll.378 forms violet colonies. The pigment is enhanced on media rich in tryptophan and yeast extracts. In nutrient broth, it forms a violet ring around the wall of the tube but no cohesive skin. The violet pigment is soluble in ethanol but insoluble in water and chloroform.

Chromobacterium violaceum SC ll.378 is mesophilic, growing in a range of 15-37OC; no growth occurs at 4OC or above 37oC. Casein is strongly hydrolyzed by the microorganism, which is oxidase positive. In the presence of Chromobacterium violaceum SC ll.378, glucose, fructose and trehalose are fermented (method according to Hugh & Leifson, l953). L-arabinose is not used by the microorganism either fermentatively or oxidatively. Hydrogen cyanide is formed by the microorganism and aesculin hydrolysis is negative.

The key characteristics described above provide a basis for the identification of the microorganism such as Chromobacterium violaceum, unlike Chromobacterium lividum, the only other species of the genus Chromobacterium listed in the 8th edition of Bergey's Manual of Determinative Bacteriology. 500 216 '27 Additional strains of Chromobacterium violaceum can also be grown to form EM5117.

The antibiotic For the production of antibiotic EM5117, Chromobacterium violaceum SC 11,378, ATCC no. 31532 at or about 250C under submerged aerobic conditions on an aqueous nutrient medium containing an assimilable carbon source and nitrogen source. The fermentation is carried out until substantial antibiotic activity is imparted to the medium, usually about 18-24 hours, preferably about 20 hours.

Using the following procedure, EM5117 can be separated from the fermentation medium and purified. After completion of fermentation, the culture broth can be centrifuged to remove mycelium or filtration can alternatively be used to remove the mycelium from the culture broth. After removal of the mycelium from the culture broth, EM5117 can be extracted therefrom. Preferably, the culture broth is extracted at pH 5 through ion pair extraction with cetyldimethylbenzylammonium chloride in methylene chloride and re-extraction to an aqueous solution of sodium iodide (adjusted to pH 5 with acetic acid). After concentrating the sodium iodide extract in vacuo, an aqueous solution of the residue can be washed with butanol. Concentration of the resulting aqueous solution to dryness gives a residue, which is dissolved as far as possible in methanol. Centrifugation can be used to separate insoluble substances, which are washed with methanol and then discarded.

Purification of the antibiotic can be accomplished by dissolving the methanol concentrate in methanol / water (1: 1) and applying the solution to a chromatography column, e.g. a column containing Sephadex G-10 in the same solvent mixture. After elution with the same mixture, active fractions are combined and concentrated to dryness. The residue is mixed with methanol and insoluble matter is filtered off and discarded.

Further purification is accomplished by applying the methanol-soluble material to a column of DEAE-cellulose. The column can be eluted with a linear gradient prepared from pH 5 sodium phosphate buffer 0.0.M and pH 5 sodium phosphate buffer 0.1M.

Active fractions are combined, concentrated and methanol insoluble material is removed and discarded.

Further purification of EM5117 was accomplished by dissolving this material in water and applying the solution to a column of Sephadex LH-20 and eluting the column with water. Active fractions are combined and concentrated. Further purification of EM5117 is then performed by dissolving the material in water, applying the solution to a column of Diaion HP-20OAG and eluting with water. Active fractions are combined and concentrated. The concentrate is dissolved in water and passed through a column of Dowex SOW-X2, the potassium form, and washed with water. The effluent can be concentrated to give a crystalline material, which is the relatively pure potassium salt of EM5117.

The above-described isolation and purification process yields the potassium salt of EM5117. Other salts can be prepared corresponding to the form of the ion exchange resin used in the final purification step.

Biological preparation of antibiotic EM5210 Salts of (R) -3 - [[N- (D-1> glutamyl) -D-alanyl1-amino] -3-methoxy-2-oxo-1-azetidinesulfonic acid (formula I, R1 is DY = glutamyl-D-alanyl and R 2 is methoxy (hereinafter referred to as EM521) can also be prepared by culturing various acetic acid bacteria.

The microorganism The microorganism Gluconobacter, species SC11.435, can be used for the production of EM52110. A subculture of the microorganism can be obtained from the permanent collection of the American Type Culture Collection, Rockville, Maryland, USA. Its availability number in the depository is ATCC no. 31581. In addition to the specific microorganism described and characterized below, it should be understood that mutants of the microorganism (eg, mutants produced using X-rays, ultraviolet radiation, or mustard gas) can also be cultured for formation. of EM5210.

Gluconobacter species SCll.435, ATCC no. 31581 can be isolated from soil moss containing the microorganism by first incubating the soil moss in a 10% aqueous solution of pectin (pH 2.5) for 7 days at 25 ° C. The organism can then be isolated by applying it to a plate with a medium containing: x Spartina patens grass extract 400 ml distilled water 600 ml yeast extract 5 g glucose 10 g raw flake agar 17.5 gx Spartina patens grass extracts are prepared by adding batch of 500 g of chopped, dry grass to 3 liters of tap water, which is brought to a boil and simmered for 30 minutes.

The medium is adjusted to pH 6.0 and sterilized in an autoclave at 120 ° C for 20 minutes. After approximately 18 hours of incubation at 25 ° C, colonies of the Gluconobacter strain SC11.435 are isolated from the pectin-enriched solution on the plate. These isolated colonies are then grown in a medium containing: yeast extract 1 g meat extract 1 g "NZ amine A" 2 g glucose 10 g agar 15 g distilled water to 1 liter The medium is adjusted to pH 7.3 and autoclaved at 120 ° C for 30 minutes.

The gluconobacter species SC11.435 is a pleiomorphic gram-negative rod, which is mobile on the basis of one to three polar flagella.

It is obligatory aerobic, catalase positive and oxidative. It can be distinguished from Pseudomonas because it is cytochrome oxidase negative and tolerant to extremely acidic conditions. These characteristics indicate that the microorganism is more closely related to the acetic acid bacteria than the true Pseudomonads.

On "BBL Trypticase" soy agar, the Gluconobacter species SCll.435 grows as a mixture of coarse and smooth colony types. The coarse type is associated with a pale yellow soluble pigment, while the smooth type is mucoid and pigmentless. Dissociation between the two the types are affected by the medium, the temperature and the storage conditions.EM5210 activity tends to decrease in cultures where the coarse component is dominant.

On "BBL Wart" agar (pH 4.8), the Gluconobacter species SC11.435 grows abundantly as suspended mucoid mucus colonies.

Similar growth is obtained on malt yeast extract agar (1% of each) adjusted to pH 4.5.

On a medium containing 1% yeast extract, 10% glucose, 3% calcium carbonate and 2.5% agar, sufficient acid is formed from the glucose to form a zone free of calcium carbonate around the growth. This is a characteristic of Acetobacter and Gluconobacter.

In the presence of the Gluconobacter species SC11.435: (i) a brown soluble pigment is formed on yeast extract-glycerol and yeast extract-calcium-lactate agar plates, (ii) acid is formed on glucose, fructose, galactose, mannose, xylose, mannitol and arabinose, but no growth or acid formation occurs on ramnose, lactose, sucrose or maltose when these sugars are incorporated into a medium according to Hugh and Leifson.

The biological production of EM52110 is not limited to the Gluconobacter species SC11.435 but is widely distributed among the acetic acid bacteria. The following cultures can each be used to produce EM52110: Acetobacter pasteurianus subsp. pasteurianum ATCC 6033 Acetobacter aceti subsp. aceti ATCC 15973 500 216 '31 Gluconobacter oxydans subsp. oxidant ATCC 19357 Gluconobacter oxydans subsp. suboxydans ATCC 23773 Gluconobacter oxydans subsp. oxidant ATCC 15178 Acetobacter aceti subsp. liquefaciens ATCC 23751 Acetobacter peroxydans ATCC 12874 Gluconobacter oxydans subsp. suboxydans ATCC 19441 Acetobacter sp. ATCC 21780 Gluconobacteroxydans subsp. industrialis ATCC 11894 The antibiotic For the production of antibiotic EM5210, the Gluconobacter species SCll.435, ATCC no. 31581 or one of the above microorganisms is grown at or about 25 ° C under submerged aerobic conditions on an aqueous nutrient medium containing an assimilable carbon and nitrogen source. The fermentation is carried out until significant antibiotic activity has been conferred on the medium, usually about 16-24 hours, preferably about 20 hours.

Using the following procedure, EM5210 can be separated from the fermentation medium and purified. After the fermentation is complete, the culture broth is centrifuged to remove bacteria and the antibiotic is removed from the supernatant of the culture broth at pH 3.7 by absorption on an anion exchange resin, e.g. Dowex 1-X2. The antibiotic is eluted from the resin with sodium chloride at about fl 4 and the eluate is concentrated and passed through a carbon column. EM5210 is then eluted from the carbon with methanol water (lzl). The active fractions are collected and dried and then placed on an anion exchange column, e.g. Dowex 1-X2, and eluted with a gradient of sodium chloride buffered at pH 4. Active fractions are concentrated and desalted on a column of a macroreticular styrene / divinylbenzene copolymer resin ("Dianion HP 2OAG"). Active fractions are eluted with water and concentrated and lyophilized and this material constitutes the sodium salt of EM5210.

The purification procedure described above gives the sodium salt of EM5210. Other salts can be obtained by exchanging the salt used to elute EM5210 in the ion exchange turf chromatography described above, e.g. using potassium chloride to obtain the potassium salt.

The following examples constitute specific embodiments of the invention.

Example 1

(S) -31 / IK2-amino-4-thiazolyl) acetylamine] -2-oxo-1-azetidinesulfonic acid, potassium salt A) (S) -3-amino-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt ( S) -2-oxo-31 [Z (phenylmethoxy) carbonyl] amine Q7-1-azetidinesulfonic acid, tetrabutylammonium salt (2 g; compare Example 4) is dissolved in 100 ml of dimethylformamide and hydrogenated for about 30 minutes with 1 g of palladium on carbon (10%) such as catalyst). The catalyst is filtered off and the dimethylformamide is removed to give the title compound as an oil. NMR (CDCl 3) 3.82 (1H, t, 1 = 5.5), 4.05 (d, 1H, d of d, / = 5.5, 2.5 cps).

B) (S) -3- [2-Amino-4-thiazolyl) acetyl] amino] -2-oxo-1-azetidine-sulfonic acid, potassium salt The above compound (2 g), 0.5 g of aminothiazol acetic acid and 0.4 g g of hydroxybenzotriazole is stirred at 0 DEG C. in 100 ml of dry dimethylformamide while a solution of 0.7 g of dicyclohexylcarbodiimide in 10 ml of dimethylformamide is added dropwise. After the addition is complete, stirring is continued for 12 hours at ZOOC. Insoluble urea is filtered off and the solvent is evaporated off in vacuo. The oily residue is treated with a solution of potassium perfluorobutanesulfonate in 20 ml of acetone at room temperature for 15 minutes. After the addition of 200 ml of dimethyl ether, the title compound precipitates and is filtered off, dried and purified by chromatography on a 300 ml HP-20 chromatography column using water as eluent. The yield is 850 mg of the title compound, melting point> 30000. 500 215 33 Example gel 2. NOTE (Z)] - 3- [XY2-amino-4-thiazolyl) [Y] hydroxy (phenylmethoxy) phosphinyl] methoxyiminozacetylphaminqf-2 -oxo-1-azetidinesulfonic acid, potassium salt (S) -3-amino-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (0.8 g; compare Example 1A) in 30 ml of dimethylformamide, 0.9 g of Yi; -2 -amino-Rf7HYloxy (phenylmethoxy) phosphinyl] methoxy] imino [4-thiazoleacetic acid, 0.3 g hydroxybenzotriazole and 0.7 g dicyclohexylcarbodiimide are stirred for 24 hours at room temperature. The precipitated urea is filtered off and the solvent is removed in vacuo.

The residual oil is treated with an equivalent amount of potassium perfluorobutanesulfonate in 10 ml of acetone. The title compound is filtered off and purified using HP-20 resin and water as eluent to give 500 mg of substance, mp 210-21 ° C, dec.

Example 3. E 3 S (Z)] - 3- [2X2-amino-4-thiazolyl) (ethoxyimino) -acetylamine] -2-oxo-1-azetidinesulfonic acid, potassium salt (S) -3-amino-2-oxo- 1-Azetidinesulfonic acid, tetrabutylammonium salt (1.5 g; compare Example 1A) in 100 ml of dimethylformamide, 0.6 g of hydroxybenzotriazole, 1 g of dicyclohexylcarbodiimide and 0.8 g of (Z) -2-amino fixr (ethoxyimino) -4-thiazoleacetic acid are stirred at room temperature for 24 hours. The solvent is distilled off and the residue is dissolved in 30 ml of acetone. The urea is filtered off and the mother liquor is treated with a solution of 2 g of potassium perfluorobutanesulfonate in 20 ml of acetone. After adding 200 ml of ether, the title compound precipitates, is filtered off and dried. Purification is performed by chromatography using an HP-20 column and water as eluent to give 1.1 g of the title compound, mp 180-1a5 ° C, dec. Example 21 ÅÉS (E)] - 3: (2ZY2-amino-4-thiazolyl) (ethoxyimino) acetyl] amine] -2-oxo-1-azetidinesulfonic acid, potassium salt. In the manner described in Example 3, but using (E) -2-amino-xr (ethoxyimino) -4-thiazoleacetic acid instead of (Z) -2-aminoxo (ethoxyimino) -4-thiazoleacetic acid, the title compound is obtained with the melting point 160-1700C after freeze-drying.

Example 5. [3S (Z) -3 - [[(2-amino-4-thiazolyl)] (2,2,2-trifluoroethoxy) imino] acetyl] amino] -2-oxo-1-azetidinesulfonic acid, potassium salt On the procedure described in Example 3 but using (Z) -2-amino-α - [(2,2,2-trifluoroethoxy) imino] -4-thiazoleacetic acid instead of (Z) -2-amino-α- ( ethoxyimino) -4-thiazoleacetic acid, the title compound is obtained, m.p. 160-17000 after lyophilization.

Example 6. [3S (Z)] - 3 - [[(2-amino-4-thiazolyl) (methoxyimino) -acetyl] amino] -2-oxo-1-azetidinesulfonic acid, potassium salt (S) -3-amino-2 -oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (prepared as described in Example 1A using 7.9 g of (S) -2-oxo-3 - [[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid, tetrabutylammonium salt) is cooled to 0 DEG C. and 3.53 g of (Z) -2-amino-α- (methoxyimino) -4-thiazoleacetic acid are added followed by a solution of 3.27 g of dicyclohexylcarbodiimide in 10 ml of dimethylformamide. The mixture is stirred for 16 hours at SOC, filtered and the solvent is removed in vacuo. The residue is dissolved in acetone and filtered. When 60 ml of a 10% solution of potassium perfluorobutanesulfonate in acetone are added, 4.7 g of crude product crystallize. The crude product is purified by chromatography on HP-20, 100-200 mesh, to give 3.0 g of the title compound, m.p. Example 21 [3S (Z)] - 3 - [[(2-amino-4-thiazolyl) [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] acetyl ] -amino] -2-oxo-1-azetidinesulfonic acid, potassium salt (1: 1) A solution of 0.005 mol (S) -3-amino-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (compare Example 1A) and 0.006 mol of (Z) -2-amino-α - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] -4-thiazoleacetic acid in 60 ml of dimethylformamide are treated with 0.7 g of hydroxybenzotriazole and 1.13 g of dicyclohexylcarbodiimide.

The mixture is stirred for about 16 hours at room temperature, filtered and the filtrate is evaporated. The residue is dissolved in 30 ml of acetone, filtered and treated with 20 ml of a solution of 10% potassium perfluorobutanesulfonate in acetone. After addition of petroleum ether, the title compound precipitates and is treated with ether and filtered to give 3.8 g of product, m.p. 19,000, dec.

Example 8. [3S (Z)] - 3 - [[(2-amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -2-oxo-1-azetidinesulfonic acid, dipotassium salt [3S (Z)] - 3 - [[(2-amino-4-thiazolyl) [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] acetyl] amino] -2-oxo 1-azetidinesulfonic acid, potassium salt (2 g; compare Example 7) is suspended in 5 ml of anisole and 25 ml of trifluoroacetic acid are added at -IOPC.

The mixture is stirred for 10 minutes at -10 ° C. Ether (100 ml) is added slowly at -10 ° C and then * SO ml of petroleum ether is added. The precipitate is filtered to obtain 1.6 g of trifluoroacetic acid salt. This is suspended in 20 ml of water at 0 ° C, adjusted to pH 5.5 with dilute potassium hydroxide and purified on an HP-20 column. The title compound is eluted with water and has a melting point of 225 ° C, decomposition. Example 9._ [3S (Z)] - 3- [1- (2-amino-4-thiazolyl) [[2- (diphenylmethoxy) -2-oxoethoxy] imino] acetyl] amino] -2- oxo-1-azetidinesulfonic acid, potassium salt Following the procedure of Example 7 but using (Z) -2- -amino-α - [[2- (diphenylmethoxy) -2-oxoethoxy] imino] -4-thiazoleacetic acid in instead of (Z) -2-amino-α - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] -4-thiazoleacetic acid the title compound is obtained with melting point 180 DEG C., decomposition.

Example 10; [ES (ZX] -3- [ZX2-amino-4-thiazolyl) (β2-methoxy-2-oxoethoxy) imine] acetyl] amino] -2-oxo-1-azetidinesulfonic acid, potassium salt (Z) -2-amino] -methoxy-2-oxoethoxy) imine] -4-thiazoleacetic acid (1.3 g) and (S) -3-amino-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (2.03 g; compare Example 1A) are dissolved in 50 ml of acetonitrile and 1.03 g of dicyclohexylcarbodiimide dissolved in 5 ml of acetonitrile are added dropwise at 0 ° C. After stirring for 15 hours and filtering the dicyclohexylurea, the solvent is distilled off. The residual oily residue is dissolved in acetone and treated with an equivalent amount of potassium perfluorobutanesulfonate. The title compound is isolated and purified by column chromatography on HP-20 using water as eluent to give the title compound, m.p. 195-198 ° C.

Exemgel ll. . . 29 g of dicyclohexylcarbodiimide for 12 hours with stirring.

The precipitated urea was filtered off and the solvent was removed in vacuo. The residual oil was treated with an equivalent amount of potassium perfluorobutanesulfonate in 20 ml of acetone. After adding 216 '37 batches of ether, the title compound was precipitated and filtered to give 2.77 g of crude product. Purification of this crude product by column chromatography using HP-20 and water / acetone (9: 1) as eluent gave the title compound, mp 155-160 ° C, dec.

Example 12. [38 (Z)] - 3- [212-amino-4-thiazolyl) [22- (1,1-dimethylethoxy) -2-oxo-1-phenylethoxyphiminiclacetylamine] -2-oxo-1-azetidinesulfonic acid, potassium salt (S) -3-Amino-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (2.25 g; compare Example 1A) in 60 ml of dimethylformamide was stirred at room temperature with 2.4 g of (Z) -2-amino-x: / Z2- (1,1-dimethylethoxy) -2-oxo-1-phenylethoxyphimino-4-thiazoleacetic acid, 1 g hydroxybenzotriazole and 1.5 g dicyclohexylcarbodiimide for 12 hours. The solvent was removed in vacuo and the residue was dissolved in 50 ml of acetone. The precipitated urea was filtered off and the mother liquor was treated with an equivalent amount of potassium perfluorobutanesulfonate. After addition of ether, the title compound crystallized and was filtered off. Purification of the compound was accomplished by HP-20 column chromatography using water / acetone (7: 3) as eluent, to give 1 g of product, m.p.> 250 DEG C., decomposition.

Example_13. 135 (Z)] - 3- [IT2-amino-4-thiazolyl) γ] 1H-tetrazol-5-ylmethoxy) amino [acetyl] amino] -2-oxb-1-azetidinesulfonic acid, potassium salt (S) -3-amino-2 oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (1.9 g; compare Example 1A) in 60 ml of dimethylformamide is treated with 1.4 g of (Z) -2-amino [1R] / [1H-tetrazol-5-ylmethoxy) imine] -4-thiazoleacetic acid, 0.7 g hydroxybenzotriazole and 1.4 g dicyclohexylcarbodiimide with stirring for 24 hours. After removal of the solvent in vacuo, the residue was dissolved in acetone and the precipitated urea was filtered off. The mother liquor was treated with an equivalent amount of potassium perfluorobutanesulfonate in 10 ml of acetone.

The title compound was precipitated by adding 200 ml of ether. Purification was performed by HP-20 column chromatography using HP-20-500 216 38 resin and water as eluent to give 1.05 g of product, m.p. 250 DEG C., decomposition.

Example 14. ÅÉS (Z)] - 3-yl-2-amino-4-thiazolyl) -phenylmethoxy) -imino] -acetyl] -amino) -2-oxo-1-azetidinesulfonic acid, potassium salt (S) -3-amino-2 -oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (1.5 g; compare Example 1A), 1.23 g (Z) -2-amino-phenylphenylmethoxy) -imine-4-thiazoleacetic acid, 0.57 g hydroxybenzotriazole and 1.4 g dicyclohexylcarbodi in 60 ml of dimethylformamide at room temperature for 24 hours. The precipitated urea was filtered off, the solvent was removed and the residue was treated with an equivalent amount of potassium perfluorobutanesulfonate in 10 ml of acetone.

After adding 200 ml of ether, the title compound precipitated and was filtered off and purified by HP-20 column chromatography using water / acetone (9: 1) as eluent to give 1 g of material having a melting point of 200 DEG C., decomposition.

Example 15.

[BS (Z)] - 3-1212-amino-4-thiazolyl) (carboxymethoxy) iminoacetylamine] -2-oxo-1-azetidinesulfonic acid, potassium salt (Izl). [38 (Z)] - 3- [XY2-amino-4-thiazolyl) j] E- (diphenylmethoxy) 2-oxoethoxy-7-imino] acetyl] amino] -2-oxo-1-azetidinesulfonic acid, potassium salt (1: 1) (1.3 g; compare Example 9) was mixed with 5 ml of anisole.

At -15 ° C, 25 ml of trifluoroacetic acid were added and the mixture was stirred for 10 minutes. Ether (100 ml) was added slowly at -10 ° C and then 50 ml of petroleum ether. The precipitate is suspended under cooling in 20 ml of water and adjusted to pH 5.0 with dilute potassium hydroxide. The product is purified by chromatography on an HP-20 column to give 3.0 g of the title compound, m.p. 230-235 ° C, dec. Example 21. ÅÉS (Z)] - 3- [12-amino-4-thiazolyl) / Z2-oxo-2- (phenylmethoxy) ethoxy] -iminacetacetaminophen-2-oxo-1-azetidinesulfonic acid, potassium salt On the described in Example 7, but using (Z) -2-amino-.beta.-oxo-2- (phenylmethoxy) ethoxy] imino [4] -thiazole acetic acid instead of (Z) -2-amino- «: 1YÉ- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxyimino] -4-thiazoleacetic acid, the title compound was obtained with a melting point of about 170 DEG C., decomposition.

Example 17. (3E [(2-amino-4-thiazolyl) (hydroxyimino) -acetyl] amine] -2-oxo-1-azetidinesulfonic acid, potassium salt A solution of 0.6 g of 90% hydroxybenzotriazole in 100 ml of dimethylformamide was stirred for one hour with 10 g of 4Å molecular sieves, filtered and the filtrate was added to a solution of 0.004 mol of (S) -3-amino-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (compare Example 1A ) in dimethylformamide. (Z) -2-Amino-qua (hydroxyimino) -4-thiazoleacetic acid (0.89 g) is added followed by the addition of 0.91 g of dicyclohexylcarbodiimide. The mixture is stirred for about 16 hours, evaporated in vacuo and the residue is dissolved in 20 ml of acetone and filtered. Addition of a solution of potassium perfluorobutanesulfonate precipitated the title compound. Chromatography on HP-20 resin gave 0.44 g of product, m.p.

Example 18. ÅÉS (ZL] -3- [ZX2-amino-4-thiazolyl) [Ycarboxymethoxy) imineacacetylamine] -2-oxo-1-azetidinesulfonic acid, potassium salt [35 (Z)] - 3-1212-amino-4 -thiazolyl) [2,2-oxo-2- (phenylmethoxy) -ethoxy] imino] acetyl] amino] -2-oxo-1-azetidinesulfonic acid, potassium salt (0.1 g; compare Example 16 is dissolved in a mixture of 5 ml of ethanol and 5 ml of water and hydrogenated at room temperature in the presence of 0.2 g of 10% palladium on carbon, after 2 hours the catalyst is filtered off and the remaining solution is lyophilized to give the title compound, m.p. 235 DEG C. (dec.). 500 216 40 Example 19.

[BS (Z)] -3- [232-amino-4-thiazolyl) -2- (1,1-dimethylethoxy) -1- (methylthio) -2-oxoethoxy] imine] acetyl] -amino-2-oxo-1 -azetidine-sulfonic acid, potassium salt In the manner described in Example 17 but using (Z) -2-aminoqu: ÅY2- (1,1-dimethylethoxy) -1- (methylthio) -2-oxoethoxy] -imino-4- thiazoleacetic acid instead of (Z) -2-amino-α & (hydroxyimino) -4-thiazoleacetic acid the title compound is obtained, m.p. 130 DEG C., decomposition.

Example V20. [81 (Z)] - 3-1212-amino-4-thiazolyl) (methoxyimino) -acetyl] aminoQ] -3-methoxy-2-oxo-1-azetidinesulfonic acid, potassium salt 3-amino-3-methoxy-2-oxo -1-azetidinesulfonic acid, tetrabutylammonium salt are dissolved in adetonitrile (20 ml) and pyridine (1 ml) and added to a vigorously stirred suspension of (Z) - (methoxyimino) -2-amino-4-thiazoleacetyl chloride in acetonitrile (20 ml) cooled to O-500. After stirring in the cold for one hour, the mixture is diluted with 0.5M solution of monobasic potassium phosphate (100 ml) (pH of the mixture is 4.8) and the solvent is removed in vacuo. The residue is taken up in a minimal amount of water containing a small amount of acetone.

Chromatography on ion exchange resin (AG 50W-X2, 100-200 mesh, K + form, 200 ml) gives the crude product as the potassium salt on elution with water. Further purification on HP-20 resin (200 ml) using water as eluent gives 59 mg of product as a powder after trituration with acetonitrile / ether and then twice with ether. The product is an amorphous powder, which melts slowly and decomposes above 15o ° c.

Analysis for ClOH 12 N 5 O 7 SC: Calculated: C 28.77 H 2.90 N 16.78 S 15.36 K 9.37 Found: C 27.77 H 2.82 N 15.87 S 13.63 K 10.100 215 41 Exemgel 21. ÄÉS- [Éx1Z), QQÅI-3- [ZX2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid, potassium salt A) (3S-trans ) -4-methyl-2-oxo-3- [ZX-phenylmethoxy) carbonyl] -amino] -1-azetidinesulfonic acid, tetrabutylammonium salt (3S-trans) -4-methyl-2-oxo-3- [ZX-phenylmethoxy) -carbonyl] aminq7- -1- azetidine sulfonic acid, potassium salt (352.4 mg) is dissolved in 20 ml of water and tetrabutylammonium hydrogen sulphate (373.5 mg) is added. The aqueous solution is extracted three times with methylene chloride and the combined extracts are dried over sodium sulfate. After removal of solvent, 534.6 mg of the title compound are obtained.

B) [35-ÅEAJZ), 4β-3-1212-amino-4-thiazolyl) (methoxyimino) -acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid, potassium salt A solution of 534, 6 mg of (38-trans) -4-methyl-2-oxo-3- [ZXphenylmethoxy) carbonylaminamine-1-azetidinesulfonic acid, tetrabutylammonium salt in 20 ml of dimethylformamide are hydrogenated with 220 mg of 10% palladium on carbon at atmospheric pressure for 2 75 hours; the hydrogen uptake is 26.3 ml. The mixture is filtered and washed twice with 2.5 ml of dimethylformamide. The filtrate and washings (total approximately 25 ml) are stirred under nitrogen with 161 mg of (Z) -dr- (methoxyimino) -2-amino-4-thiazoleacetic acid, 136 mg of N-hydroxybenzotriazole and 164.8 mg of dicyclohexylcarbodiimide. The mixture is stirred under nitrogen for about 16 hours. The dimethylformamide is removed in vacuo and the gummy residue is dissolved in acetone and filtered to remove urea. To the filtrate is added a solution containing 272 mg (0.8 mmol) of perfluorobutanesulfonic acid, potassium salt in 0.8 ml of acetone. The slurry is diluted with an equal volume of ether and filtered to give 325.5 mg of crude product, which is purified by chromatography on 75 ml of HP-20AG.

Elution with 400 ml of water and 400 ml (9: 1) of water / acetone (50 ml fractions) gives 335 mg in fractions 3-10. After trituration with acetone / hexane, 97.3 mg of an analytical sample from fractions 3-5 are obtained. Similar trituration of fractions 6-10 gives an additional 90.4 mg of product as a solid. 500 216 42 Analysis: ClOH 12 N 5 O 6 S 2 K Calculated: C 29.92 H 3.01 N 17.45 S 15.97 K 9.74 Found: C 30.32 H 3.49 N 15.82 S 13.95 K 10.45 1 H NMR (D 2 O) 1.57 (3H, d, / = 7), 3.97 (3H, S), 4.30 (1H, d of q, J = 7.3), 4.70 (1h, d, J = 7), 6.95 ppm (1H, S).

Example 22. [ss-fsalz), M] [- [(fl2-amino-4-thiazolyl) [(1-carboxy-1-methyl-ethoxy) imineacetyl] -4-methyl-2-oxo-1-azetidinesulfonic acid, dipotassium salt A) N-benzyloxy-t-boc-threoninamide A solution of 8.76 g of t-boc-threonine and the free amine from 6.4 g of O-benzylhydroxylamine.HCl (ethyl acetate / sodium bicarbonate liberation) in 100 ml of tetrahydrofuran is treated with 6.12 g of N-hydroxybenzotriazole and 8.24 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran. The mixture is stirred under nitrogen for 26 hours, filtered and evaporated in vacuo. The residue is chromatographed on 300 g of silica gel in a column (eluting with chloroform and chloroform / ethyl acetate (3: 1)) to give 7.2 g of compound. Crystallization from ether / hexane gives 4.18 g of the title compound. § (38-trans) -N-benzyloxy-3-t-butoxycarbonylamino-4-methyl-azetidinone A solution of 12.67 g of N-benzyloxy-t-boc-threonine amide, 11.5 g of triphenylphosphine and 6 23 ml of diethyl azodicarboxylate in 380 ml of tetrahydrofuran are stirred under nitrogen for about 16 hours.

The solution is evaporated and chromatographed on a 900 g silica gel column. Elution with chloroform / ethyl acetate (3: 1) gives 13.69 g of compound, which is crystallized from ether / hexane to give 9.18 g of the title compound.

C) (3S-trans) -3-t-butoxycarbonylamino-1-hydroxy-4-methylazethidinone A solution of 9.18 g (3S-trans) -N-benzyloxy-3-t-butoxycarbonylamino-4- Methyl azetidinone in 300 ml of 95% ethanol is stirred in an atmosphere of hydrogen with 1.85 g of 10% palladium on carbon. After 500 minutes, the slurry is filtered and evaporated in vacuo. The residue is recrystallized from ether / hexane to give 5.12 g of the title compound.

D) (3S-trans) -3-t-butoxycarbonylamino-4-methylazetidinone A solution of 4.98 g of (3S-trans) -3-t-butoxycarbonylamino-1-hydroxy-4-methylazetidinone in 200 ml of methanol is treated with 132 ml of 4.5M ammonium acetate and then with 66 ml of 1,5M titanium trichloride and stirring for 4.5 hours. The aqueous solution is diluted with an equal volume of 8% sodium chloride and extracted with ethyl acetate to give 3.48 g of crude product. Recrystallization from ether / hexane gives 3.3 g of the title compound.

E) (3S-trans) -3-benzyloxycarbonylamino-4-methylazetidinone A solution of 3.3 g of (3S-trans) -3-t-butoxycarbonylamino-4-methylazetidinone in 10 ml each of dichloromethane and anisole is cooled to 0 ° C and 112 ml of trifluoroacetic acid is added.

The solution is stirred for 90 minutes and evaporated in vacuo (benzene is added and evaporated three times). The residue is dissolved in 70 ml, acetone and the solution is adjusted to pH 7 with 5% sodium bicarbonate solution. A total of 5.33 g of benzyl chloroformate is added over one hour at pH 6.5-7.5. The mixture is stirred for 30 minutes at pH 7, diluted with 100 ml of saturated brine and extracted with ethyl acetate (three 400 ml portions). The residue obtained by evaporation is chromatographed on a one liter silica gel column. Elution with chloroform / ethyl acetate (4: 1) gives 2.19 g of compound. Crystallization from ether / hexane gives 1.125 g of the title compound.

F) (35-trans) -4-methyl-2-oxo-3- [21-phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid, tetrabutylammonium salt A solution of 600 mg (3S-trans) -3-benzyloxycarbonylamino-4-methylazetidinone in 2 ml of dimethylformamide is cooled to 0 ° C and 4 ml of 0.8M sulfur trioxide in dimethylformamide are added. The solution is stirred at room temperature under nitrogen for one hour and poured into 80 ml of cold 0.5M monobasic potassium phosphate (adjusted to pH 5.5). The solution is extracted with three 50 ml portions of methylene chloride (discarded) and 868 mg of tetrabutylammonium bisulfate are added. The resulting solution is extracted with four 75 ml portions of methylene chloride. The combined organic layers are washed with 8% aqueous sodium chloride solution, dried and evaporated in vacuo to give 1.54 g of the title compound.

G) [ss- [aaum, 44]] - 3 - [[(z-amino-2-z-thiazolyl) -β-diphenylmethoxycarbonyl-1-methylethoxy) imine] -acetylamine-4-methyl-2-oxo-1-azetidinesulfonic acid Potassium salt A solution of 1.54 g (38-trans) -Q-methyl-2-oxo-3-12] phenylmethoxy) -carbonylamino] -1-azetidinesulfonic acid, tetrabutylammonium salt in 45 ml of dimethylformamide is stirred in an atmosphere of hydrogen with 800 mg 10% palladium on carbon for 2 hours. The catalyst is filtered and the filtrate is stirred for about 16 hours with 1.24 g of (Z) -2-amino-methyl (1H-diphenylmethoxycarbonyl-1-methylethoxy) imineQ7-4-thiazoleacetic acid, 0.4 g of N-hydroxobenzotriazole and 580 mg of dicyclo hexylcarbodiimide. The slurry is evaporated in vacuo and the residue is triturated with 20 ml of acetone and filtered. The filtrate (plus 2 ml of the washing liquids) is treated with 868 mg of potassium perfluorobutanesulfonate in 3 ml of acetone. Dilution with 75 ml of ether gives a solid, which is isolated by decantation of the mother liquor, trituration with ether and filtration to give 0.91 g of the title compound. The mother liquor is diluted with an additional 100 ml of ether to give a second crop, 0.45 g, of the title compound.

H) EES- / EXÅZ), α, β-3- [242-amino-4-thiazolyl] -carboxy-1- [1-methylethoxy] imine] -acetylamine-4-methyl-2-oxo-1-azetidinesulfonic acid, dipotassium salt slurry of 140 mg [58-XEAJZ), QQZ / -3- (IT2-amino-4-thiazolyl) [1,1-diphenylmethoxycarbonyl-1-methylethoxy] imino] -acetyl] amineQ7- -4-methyl-2-oxo-1-azetidinesulfonic acid , potassium salt (first harvest) in 0.5 ml of anisole is stirred at -12 ° C under nitrogen and 2.5 ml of cold (-10 ° C) trifluoroacetic acid is added. After 10 minutes, 10 ml of ether and 5 ml of hexane are added and the resulting slurry is stirred for 5 minutes at -12 ° C and allowed to warm to room temperature. The solid is isolated by centrifugation and washed twice with ether. A solution of this solid in 5 ml of cold water is immediately adjusted to pH 5.5 with 0.4N potassium hydroxide and then applied to an 80 ml HP-20AG column. Elution with water gives 72 mg of the title compound in fractions (10 ml) 7-1 after evaporation (acetonitrile is added and evaporated three times) and trituration with ether, m.p. about 250 ° C (dec.).

Analysis: C 13 H 15 N 5 O 8 S 2 K 2: Calculated: C 30.51 H 2.95 N 13.69 S 12.53 K 15.28 Found: C 29.63 H 3.20 N 12.96 S ll, 94 K 12.78 NMR ( D 2 O) 1.46 (S, 6H), 1.58 (1H, d, / = 7), 4.28 (1H, d of q, / = 7, 2.5), 4.67 (1H, d , J = 2), 6.95 ppm (S, 1H).

The remaining 1.22 g of [35- [3xαZ), (dZ] -3-1212-amino-4-thiazolyl) .beta.-diphenylmethoxycarbonyl-1-methylethoxy) -imino] acetyl] amine] -4-methyl-2 -oxo-1-azetidinesulfonic acid, the potassium salt (harvests 1 and 2) is treated as above (4.2 ml anisole, 16 ml trifluoroacetic acid, 13 minutes at -15 ° C). Chromatography on a 300 ml HP-20AG column gives 694 mg of the title compound in fractions (60 ml) 6-9 after treatment as above.

Example 23.

In the manner described in Example 15 but using the compound listed in column I below instead of [3S (ZL7- -3- [212-amino-4-thiazolyl)] -2- (diphenylmethoxy) -2-oxoethoxy] imino] -acetyl] amino] -2-oxo-1-azetidinesulfonic acid, potassium salt, the compound listed in column II is obtained. 500 216 46 mc fl c fi møwøcßm .U mm fi uxcsmu fi mëm .ñwn fi v a fi mmšø fifi mx _mu> mcOwH fl mc fl UHuwNm | H | 0N0 | N | Nd: HEmNA> uwomNd: fl EHNwflv uum | 1HxonHm «N \ ^ H> Ho-HH |« | o = Hem | -N \ r ~ | NHNVmm \ HH »Hmmm ^ mH Hmgämxw wmv .u fl mwäø flfi mx _mu> mcowH: mcHUHumNm1H: oxo | N | \ dcHEm A A> fi \ Ax0umOxo | N | 1 ^ oHHH> »weV | H | ^ HxøHwH> HweHw | H.HV | mN \ | ^ H> Ho ~« H »« «| ocHe @ | -m \ | mN ^ Nvwww H» Hmmm .mm 500 216 ' 47 Example Gel 24. [3d (Z), 4a] -3 - [[(2-amino-4-thiazolyl) -methoxyimino) acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid, potassium salt A solution of 51.8 mg of (cis) -4-methyl-2-oxo-3 - [[(phenylmethoxy) carbonyl] amino] -1-azetidinesulfonic acid, potassium salt and 51 mg of tetra-n-butylammonium bisulfate in 5 ml of water are extracted with methylene chloride ( four 10 ml portions) to obtain 81 mg of oil. This is stirred in an atmosphere of hydrogen for two hours with 40 mg of 10% palladium on carbon in 4 ml of dimethylformamide. The catalyst is filtered off and washed with 1 ml of dimethylformamide. The filtrate and washings are combined and stirred for about 16 hours with 31 mg of (Z) -2-amino-α- (methoxyimino) -4-thiazoleacetic acid, 27 mg of N-hydroxybenzotriazole and 31.5 mg of dicyclohexylcarbodiimide.

The solution is evaporated in vacuo and the residue is triturated with 3 ml of acetone. The resulting slurry is centrifuged and the liquid is treated with 51 mg of potassium perfluorobutanesulfonate. Dilution with 5 ml of ether and filtration gives a solid.

Chromatography on HP-20 AG (40 ml) gives Rydon-positive material in fractions (20 ml) 3-5 (elution with water). Evaporation and ether trituration give 23 mg of product as a hygroscopic solid: Analysis: CHN 0 SK: 10 12 5 6 2 Calculated: C 29.91 H 3.01 N 17.44 Found: C 29.30 H 3.31 N 16 , 66 NMR (D 2 O) 1.40 (3H, d, / = 7), 3.97 (3H, S), 4.46 (1H, apparently pentet, J = 7), 5.37 (1H, d, / = 7), 6.97 ppm '(1H, S).

Example Gel 25. [3S- [3a (Z), 4G] 1-3 - [[2-amino-4-thiazolyl) -methoxyimino) acetyl] -amino-4-methyl-2-oxo-1-azetidinesulfonic acid, potassium salt En solution of 201 mg of (Z) -2-amino-α- (methoxyimino) -4-thiazoleacetic acid and 153 mg of N-hydroxy-benzotriazole monohydrate in 3 ml of dimethylformamide is treated with 206 mg of dicyclohexylcarbodiimide.

The mixture is stirred at room temperature for 20 minutes under nitrogen and a solution of 180 mg (3S-cis) -3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid and 0.14 ml of triethylamine in 2 ml of dimethylamine. formamide is added (an additional ml of dimethylformamide is used for rinsing) and the mixture is stirred for about 16 hours. The slurry is evaporated in vacuo, triturated with 12 ml of acetone, centrifuged and the liquid treated with 338 mg of potassium perfluorobutanesulfonate. Dilution with 10 ml of ether and filtration gives a solid product, which is chromatographed on 200 ml of HP-20 resin and eluting with water. Fractions (20 ml each) 18-30 are combined and lyophilized to give 274 mg of the title compound as a hygroscopic solid.

Analysis: ClOH12N5O6S2K.

Calculated: C 29.91 H 3.01 N 17.44 Found: C 30.03 H 3.21 N 17.06 NMR (D 2 O) 1.40 (3H, d, J = 6.5), 3.98 (3H, S). Exemgel 26. [.alpha .- (alpha], 44 [mu] -3- [2,2-amino-4-thiazolyl) -1,2,1-aamethyl] -2- [14-nitrophenyl) -methoxy] -2-oxoethoxy] -imining] acetylfamingzl -4-methyl-2-oxo-1-azetidinesulfonic acid, potassium salt To a slurry of (3S-trans) -3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid (0.36 g, in dry dimethylformamide 30 ml) under nitrogen at 2600 add triethylamine (309, ¿d) After about 5 minutes a clear solution is obtained and (Z) -2-amino1x; [Z1,1-dimethyl-2- [Y4-nitrophenyl ) - Methoxy-2-oxoethoxy-7-imining-4-thiazoleacetic acid (0.86 g) is added followed by N-hydroxybenzotriazole (0.334 g) and dicyclohexylcarbodiimide (0.453 g). The mixture is stirred for 12 hours at 26 ° C, after which the solvent is removed in vacuo and the residue is triturated with acetone (30 ml). After stirring for 5 minutes, the solids are removed and the filtrate is treated with potassium perfluorobutanesulfonate (3.680 g) in acetone (5 ml).

Addition of ether (about 40 ml) gives a precipitate, which is collected and dried in vacuo (1.073 g; a second harvest 0.066 g; a total of 1.14 g).

Analysis: c20H21N6olOs2K-1 H2O Calculated: C 38.33 H 3.70 N 13.41 S 10.23 K 6.24 Found: C 38.30 H 3.63 N 13.41 S 9.88 K 5.98 500 215 49 ExemEel527. 3g§Z), 4g] -3- [ZX2-amino-4-thiazolyl) [γ1-carboxy-1-methylethoxy) -iminingZacetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid, potassium salt (1: 2 ) A) jauz), Qgz-3-122-amino-4-thiazolyl) η 5 - diphenylmethoxycarbonyl-1-methylethoxy) imingzacetylzamine -4-methyl-2-oxo-1-azetidinesulfonic acid, potassium salt A solution of (cis) - 4-Methyl-2-oxo-3- [21-phenylmethoxy) carbonylamino] -1-azetidinesulfonic acid, tetrabutylammonium salt (201 mg; prepared from the corresponding potassium salt as described in Example 24) in 5 ml of dimethylformamide is stirred with 90 mg of 10% palladium on calcium carbonate in an atmosphere of hydrogen for 2 hours. The slurry is filtered and the filtrate is stirred for about 16 hours with 146 mg of (Z) -2-aminoxyl-diphenylmethoxycarbonyl-1-methylethoxy) imino] -4-thiazoleacetic acid, 73 mg of dicyclohexylcarbodiimide and 51 mg of N-hydroxybenzotriazole under nitrogen.

The slurry is evaporated in vacuo and triturated with 4 ml of acetone. The slurry is filtered and the solid is washed twice with 2 ml portions of acetone. The felt seam and the washing liquids are combined and treated with 113 mg of potassium perfluorobutanesulfonate. Dilution with 24 ml of ether gives a solid which is isolated by centrifugation and washed three times with ether to give 186 mg of the title compound.

B) [3a (Z), 4a] -3 - [[(2-amino-4-thiazolyl) [1-carboxy-1-methylethoxy] -imino] acetyl] amino] -2-methyl-4-oxo-1 -azetidinesulfonic acid, potassium salt (1: 2) A slurry of 186 mg [3a (Z), 4a] -3 - [[2-amino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl ] amino] -4-methyl--2-oxo-1-azetidinesulfonic acid, potassium salt in 0.6 ml of distilled anisole is cooled to 120 ° C and 3.0 ml of distilled trifluoroacetic acid (at -10 ° C) is added. The solution is stirred for 10 minutes and 12 ml of ether are added followed by 6 ml of hexane. After 5 minutes at -10 ° C and stirring for 15 minutes at room temperature, the solid is isolated by centrifugation and washed four times with ether to give 141 mg of material. This is dried in vacuo, pulverized, dissolved in 5 ml of cold water and immediately adjusted to pH 5.6 with 0.4N potassium hydroxide. The solution is applied to a 100 ml HP-20AG column and eluted with water. Fractions (10 ml) 8-12 are combined and evaporated in vacuo (acetonitrile is added three times and evaporated). The residue is triturated with ether to give 10.7 mg of product as a hygroscopic solid.

Analysis: CHN 0 S '2K: 13 15 5 8 2 Calculated: C 30.51 H 2.95 N 13.69 S 12.53 K 15.28 Found: C 30.1 H 3.26 N 13.35 S 12.12 K 15.02 Example V28. [38- [3G (Z) 1461] -3 - [[(2-amino-4-thiazolyl) - [11-carboxy-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1 -azetidine sulfonic acid [35- [3a (Z), 4β]] - 3 - [[(2-amino-4-thiazolyl) - [(1-carboxy-1-methylethoxy) imino] acetyl] amino] - 4-Methyl-2-oxo-1-azetidinesulfonic acid, dipotassium salt (87.3 mg, compare Example 22) is dissolved in 1.38 ml of water, cooled to 0 ° C, treated with 0.34 ml of 1N hydrochloric acid and the crystals formed are separated by centrifugation. .

The wet solid is dissolved in methanol, filtered, concentrated to about 0.5 ml and mixed with 1 ml of water to give 55.9 mg of the title compound.

Example 29. [3S- [3a (Z), 4β]] - 3 - [[(2-amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] -4-methyl-2- oxo-1-azetidinesulfonic acid, sodium salt A 99.7 mg sample of [3S- [3a (Z), 4B]] - 3 - [[(2-amino-4-thiazolyl) - [(1-carboxy-1-methylethoxy) ) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid is mixed with 0.207 ml of 1N sodium hydroxide and the resulting mixture is gently heated to dissolve the remaining solid. Water is azeotroped with acetonitrile and the residue is crystallized from a mixture of 0.5 ml of methanol (to dissolve the residue) and 1 ml of acetonitrile to give 81.8 mg of solid. A second recrystallization from 0.8 ml of methanol gives 47.9 mg, a third from 0.24 ml of methanol and 0.24 ml of absolute ethanol gives 44.8 mg and a fourth from 0.225 ml of methanol and 0.225 ml of absolute ethanol 500 216 51 ger 38.8 mg. The solid is dried at 2000 and 0.01 mm Hg for 18 hours and then equilibrated with atmospheric humidity for 24 hours to give 40.9 mg of the title compound.

Example 30. [3S- [3a (Z), 4a]] - 3- [1- (2-amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4- methyl 2-oxo-1-azetidinesulfonic acid, potassium salt (1: 2) A) [3S- [3a (Z), 4a]] - 3 - [[(2-amino-4-thiazolyl) - [(1-diphenylmethoxy) carbonyl-1-methylethoxy) imino] -acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid, potassium salt A solution of 440 mg (Z) -2-amino-α - [(1-carboxy-1) -methylethoxy) -imino] -4-thiazoleacetic acid and 153 mg of N-hydroxybenzotriazole monohydrate in 3 ml of dimethylformamide are treated with 206 mg of dicyclohexylcarbodiimide. The mixture is stirred at room temperature for 30 minutes under nitrogen and a solution of 180 mg of (3S-cis) -3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid and 0.14 ml of triethylamine in 2 ml of dimethylformamide is added (an additional ml of dimethylformamide was used for rinsing) and the mixture was stirred for about 16 hours. The slurry is evaporated in vacuo and triturated with 12 ml of acetone. The slurry is filtered and the solid is washed with acetone (two 3 ml portions). The filtrate and washings are combined and treated with 338 mg of potassium perfluorobutanesulfonate. Dilution with 30 ml of ether gives a gummy solid which slowly solidifies. The solid is filtered and washed with ether to give 656 mg of the title compound.

B) [3S- [3a (Z), 4u]] - 3 - [[(2-amino-4-thiazolyl) - [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4-methyl- 2-oxo-1-azetidinesulfonic acid, potassium salt (1: 2) A slurry of 656 mg [38- [3a (Z), 4a]] - 3- [I (2-amino-4-thiazolyl) [ (1-diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid, potassium salt in 2.3 ml of distilled anisole is cooled to -12 ° C and 11.5 ml trifluoroacetic acid (pre-cooled to -10 ° C) is added. The solution is stirred for 15 minutes and 46 ml of ether are added followed by 23 ml of hexane. After 5 minutes at -10 ° C and stirring for 15 minutes at room temperature, the solid is filtered and washed with ether to give 457 mg of a very hygroscopic gummy substance. This is dissolved in 6 ml of cold water and immediately adjusted to pH 5.6 with 0.4N potassium hydroxide solution.

The solution is applied to a 200 ml HP-20 resin column and eluted with water. Fractions (50 ml each) of 7-11 are combined and lyophilized to give 239 mg of the title compound as a solid.

Analysis: CHONSK '1/2 HO: 13 15 8 5 2 2 2 Calculated: C 29.99 H 3.10 N 13.45 S 12.32' Found: C 29.94 H 3.30 N 13.30 S 1.193 NMR (D 2 O) 1.44 (3H, d, / = 75), 1.46 (6H, S), 4.48 (1H, d of t, dl Example 31. [3+ (Z)] -3 - [[(2-amino-4-thiazolyl) (methoxyimino) -acetyl] amino] -4,4-dimethyl-2-oxo-1-azetidinesulfonic acid, potassium salt A solution of N-hydroxybenzotriazole hydrate (50 mg) and (Z) -2-Amino-α- (methoxyimino) -4-thiazoleacetic acid (0.323 mmol) in 0.5 ml of dimethylformamide is treated with 67 mg of dicyclohexylcarbodiimide under argon at room temperature, the resulting mixture is stirred for one hour after which (1) -3-Amino-4,4-dimethyl-2-oxo-1--azetidinesulfonic acid (57 mg; compare Example 153) is added as a solid followed by dropwise addition of triethylamine (0.05 ml). The reaction mixture is stirred at room temperature. run for 16 hoursf The dimethylformamide is removed under high vacuum at 30 ° C and the residue is slurried in 4 ml of acetone and filtered.

The filter cake is washed with an additional 4 ml of acetone and potassium perfluorobutanesulfonate (85 mg) is added to the filtrate followed by ether. Trituration of the resulting gummy substance with ether gives 40 mg of a brownish solid, which is chromatographed on a 70 ml HP-2OAG column. Elution with water gives 20 mg of the title compound in fractions (5 ml) 16-40 after evaporation, trituration with 1z1 acetone / hexane and drying, melting point 220 DEG C. (decomposition). Analysis: C 11 H 14 N 5 O 6 S 2 -K: Calculated: C 31.80 H 3.40 N 16.86 S 15.43 Found: C 29.47 H 3.48 N 14.98 S 13.35 Example 32. ( 3S-trans) -3 - [[(2-amino-4-thiazolyl) oxoacetyl] amino] -4-methyl--2-oxo-1-azetidinesulfonic acid, potassium salt To a solution of diphenylphosphinyl chloride (1.85 g) in dry dimethylformamide (15 ml) cooling in an ice / methanol bath (-1 ° to -ZOOC) is added (2-amino-4-thiazolyl) glyoxylic acid, triethylamine salt (2.4 g). After stirring for 0.5 hour, a solution of (3S-trans) -3-amino-4-methyl-2-oxo-1-azetidinesulfonic acid (1.08 g; and triethylamine (1.92 ml) in dry dimethylformamide (5 ml) to the cold mixed anhydride solution and the reaction mixture is stirred at 5 ° C for 24 hours The solvent is removed in vacuo, the residual dark oil is dissolved in water and chromatographed on Dowex 50X-2-400 resin (Kæ form After elution with water (15 ml fractions), the crude product is collected in fractions 13-27 (3.37 g) Chromatography on HP-20 resin (200 ml), eluting with water (15 ml fractions). fractions) gives the desired product in fractions 18 to 26. Removal of water in vacuo gives the title compound as an amorphous powder.

Analysis: C 9 H 9 N 4 O 6 S 2 K (372.42): Calculated: C 29.02 H 2.44 N 15.04 S 17.22 K 10.50 Found: C 28.87 H 2.62 N 14.85 S 15.09 K 10.81 Example 33.

[BS- [3a (2) .4ß]] - 3- [1- (2-amino-4-thiazolyl) [[2- (diphenylmethoxy) -2-oxoethoxy] imino] acetyl] amino] -2-methyl- 4-oxo-1-azetidinesulfonic acid, potassium salt In the manner described in Example 25 but using (Z) -2-amino-α - [[2- (diphenylmethoxy) -2-oxoethoxy] imino] -4-thiazole - acetic acid instead of (Z) -2-amino-α- (methoxyimino) -4-thiazole-acetic acid and first treatment of (3S-cis) -3-amino-4-methyl--2-oxo-1-azetidine sulfonic acid with triethylamine the title compound is obtained, melting point 155-16000, decomposition. Example 34- [3S (Rx)] - 3 - [[[[(4-amino-2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl] amino] -4-methyl-2- oxo-1-azetidinesulfonic acid, potassium salt [3S (Rx)] - [4 - [[[2 - [(4-methyl-2-oxo-1-sulfo-3-azetidinyl) amino] -2-oxo-1-phenylethyl ] amino] -carbonyl] -2,3-dioxo-1-piperazinyl] -carbamic acid, phenylmethyl ester, potassium salt is hydrogenated using gaseous hydrogen and 10% palladium on carbon as catalyst to obtain the title compound, melting point 165 ° C, decomposition .

Example 35. [3S (Z)] - 3 - [[(2-amino-4-thiazolyl)] [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -2-oxo-1-azetidinesulfonic acid, potassium salt (1: 2) [3S (Z)] - 3 - [[(2-amino-4-thiazolyl) [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino] acetyl] amino] -2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (compare Example 7) is deprotected using trifluoroacetic acid and anisole to give the title compound, m.p. 185 DEG C., decomposition, after conversion to the disodium salt with aqueous sodium hydroxide solution and sodium hydroxide solution. -20.

Example 36. (trans, Z) -3 - [[(2-amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4-ethyl-2-oxo-1- azetidinesulfonic acid, dipotassium salt A) (trans, Z) -3 - [[(2-amino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4-ethyl-2- oxo-1-azetidinesulfonic acid, dipotassium salt (trans) -3-amino-4-ethyl-2-oxo-1-azetidinesulfonic acid (0.55 g) and 335 mg of triethylamine are dissolved in 50 ml of dry dimethylformamide.

(Z) -2-Amino-Q - [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] -4-thiazoleacetic acid (1,4 g) is added with stirring at 0 ° C followed by 450 mg of hydroxybenzotriazole and then 0.69 g of dicyclohexylcarbodiimide . After stirring for about 16 hours at 0 ° C, the flask is evacuated. Dry acetone (25 ml) is added to the solid with stirring. The mixture is filtered and 0.94 g of potassium perfluorobutanesulfonaf is added to the filtrate followed by 100 ml of ether. After storage for one hour at 0 DEG C., the solid is filtered, washed with ether and dried in vacuo to give 1.58 g of the title compound.

B) (trans, Z) -3 - [[(2-amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4-ethyl-2-oxo-1- azetidinesulfonic acid, dipotassium salt To a suspension of 1.31 g (trans, Z) -3 - [[(2-amino-4-thiazolyl) + [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4 -ethyl-2-oxo-1-azetidinesulfonic acid, dipotassium salt in 10 ml of anisole is added 5 ml of trifluoroacetic acid over a 10-minute period at -15 ° C. After stirring for 2 hours at -10 ° C, a clear solution is obtained. At -30 ° C 80 ml of dry ether are added and the precipitate obtained is filtered and then treated with 5 ml of water. The pH is adjusted to 5.5 with 1N potassium hydroxide at 0 ° C and the mixture is filtered to remove unconverted starting material. The filtrate is chromatographed on HP-20 with water as eluent. Lyophilization gives 185 mg of the title compound, m.p. 160 ° C, decomposition.

Example Gel 37. [3S (Z)] - 3 - [[(2-amino-4-thiazolyl) [(4-hydroxy-4-oxobutoxy) iminolacetylamino] -2-oxo-1-azetidinesulfonic acid, potassium salt Deprotection of [BS (z)] -3 - [[(2-amino-4-thiazolyl) [H- (diphenylmethoxy) -4-oxobutoxy] imino] acetyl] amino] -2-oxo-1-azetidinesulfonic acid, potassium salt ( compare Example 166) using trifluoroacetic acid and anisole to give the title compound, m.p.

Example Gel 38. [3S- [3a (Z), 4β]] - 3 - [[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -4-cyclohexyl-2-oxo-1-azetidinesulfonic acid, Potassium salt [38-trans] -3-amino-4-cyclohexyl-2-oxo-1-azetidinesulfonic acid (0.25 g) is dissolved in 30 ml of dry dimethylformamide and 0.12 triethyl-amine with stirring. When a clear solution is obtained, (Z) -2-amino-α- (methoxyimino) -4-thiazoleacetic acid (0.2 g), 0.16 g of hydroxybenzotriazole and 0.42 g of dicyclohexylcarbodiimide are added. Stirring is continued for 48 hours at room temperature. The precipitated urea is filtered off and the solvent is removed in vacuo. The residue is dissolved in 10 ml of acetone and 0.41 g of potassium perfluorobutanesulfonate is added. After adding 50 ml of ether, the title compound is precipitated and filtered off. Column chromatography using HP-20 and water / acetone (9: 1) as eluent gives 0.36 g of product, m.p. 200-205 ° C (after lyophilization).

Example 39. [3S- [3a (Z), 4B]] - 3 - [[(2-amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4- cyclohexyl-2-oxo-1-azetidinesulfonic acid, dipotassium salt A) [3S- [3a (Z), 4β]] - 3 - [[(2-amino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1) -methylethoxy) imino] acetyl] amino] -4-cyclohexyl-2-oxo-1-azetidinesulfonic acid, potassium salt [3S-trans] -3-amino-4-cyclohexyl-2-oxo-1-azetidinesulfonic acid (0.2 g Dissolve in 30 ml of dimethylformamide and 0.09 g of triethylamine with stirring Hydroxybenzotriazole (0.2 g), 0.30 g of (Z) -2-amino-α - [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] - 4-Thiazoleacetic acid and 0.33 g of dicyclohexylcarbodiimide are added and stirring at room temperature is continued for 12 hours. The precipitated urea is filtered off and the mother liquor is evaporated to dryness. The residual oil is dissolved in 5 ml of acetone, treated with 0.3 g of potassium perfluorobutanesulfonate and poured into 100 ml of ether with stirring. [3S- [3a (Z), 4β]] - -3 - [[(2-amino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4-cyclohexyl- 2-Oxo-1-azetidinesulfonic acid, potassium salt (0.6l g) is precipitated and filtered off.

B) [35- [3a (Z), 4β]] - 3 - [[(2-amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4-cyclohexyl-2 -oxo-1-azetidine-sulfonic acid, dipotassium salt [3S- [3a (Z), 4B]] - 3 - [[(2-amino-4-thiazolyl) [(1-diphenylmethoxycarbonyl-1-methylethoxy) imino] acetyl] amino] -4-cyclohexyl-2-oxo-500 216 '57 -1-azetidinesulfonic acid, potassium salt (0.6l g) is suspended in 6 ml of anisole, cooled to -15 ° C and 5 ml of trifluoroacetic acid are added dropwise with stirring. The temperature is maintained for one hour and then lowered to -30 ° C. Approximately 100 ml of dry ether is added at such a rate that the temperature does not exceed -10 ° C. The precipitated compound is filtered off and chromatographed using HP-20 resin and water / acetone (9: 1) as eluent to give 0.3 g of the title compound, m.p. 111-120 ° C, decomposition (after lyophilization).

Example 40. (trans, Z) -3 - [[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -4-ethyl-2-oxo-1-azetidinesulfonic acid, potassium salt On the one described in Example 36 method, Part A, but using (Z) -2-amino-α- (methoxyimino) -4-thiazoleacetic acid instead of (Z) -2-amino-α - [(1-diphenylmethoxycarbonyl-1-methylethoxy) ) - imino] -4-thiazoleacetic acid gives the title compound, m.p. 190 DEG C., decomposition.

Example 41. (i) - (trans, Z) -3 - [[2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-oxo-4-phenyl-1-azetidinesulfonic acid, potassium salt A solution of N-hydroxybenzotriazole hydrate (52 mg) and (Z) -2-amino-α- (methoxyimino) -4-thiazoleacetic acid (69 mg) in dimethylformamide (0.3 ml) are treated with solid dicyclohexylcarbodiimide under argon (70 mg) at room temperature. The resulting mixture is stirred for one hour, (1) - (trans) -α-amino-2-oxo-4-phenyl-1-azetidinesulfonic acid (75 mg; compare Example 181) is added as a solid followed by triethylamine dropwise (0.05 ml). The reaction mixture is stirred at room temperature for 23 hours. The dimethylformamide is removed under high vacuum at 30 ° C and the residue is triturated with 2 ml of acetone and filtered.

The filter cake is washed with additional acetone (two 3 ml portions) and potassium perfluorobutanesulfonate (86 mg) is added to the filtrate.

Dilution with 10 ml of ether gives a gummy solid which is triturated, washed with acetone and hexane to give 82 mg of the title compound as a solid after drying. 500 216 58 Analysis: C 15 H 14 N 5 O 6 S 2 -K Calculated: C 40.26 H 3.16 N 15.65 S 14.33 K 8.74 Found: C 38.60 H 3.19 N 15.07 S 13.87 K 7 Exeggel 42. (cis, Z) -3 - [[(2-amino-4-thiazolyl) (methoxyimino) -acetyl] amino] -2-oxo-4-phenyl-1-azetidinesulfonic acid, potassium salt (cis) - 2-Oxo-4-phenyl-3 - [(phenylacetyl) amino] -1-azetidinesulfonic acid, potassium salt (560 mg) is dissolved in 5 ml of ethanol and hydrogenated with 10 mg of phatina oxide catalyst in an atmosphere. After stirring for one hour, the catalyst is removed through a Millipore filter with Celite; catalyst particles pass through the filter to form a black filtrate.

Ethanol is removed under reduced pressure and the residue is dissolved in 4 ml of dimethylformamide. N-hydroxybenzotriazole monohydrate (168 mg), 221 mg of (Z) -2-amino-α- (methoxyimino) -4-thiazoleacetic acid and 227 mg of dicyclohexylcarbodiimide are added and the mixture is stirred for about 16 hours under nitrogen. The slurry is evaporated in vacuo and triturated with 15 ml of acetone. The resulting slurry is filtered through a Millipore filter with Celite and the filtrate is treated with 372 mg of potassium perfluorobutanesulfonate.

When 1.5 ml of ether is added, a gummy substance separates.

Liquid is removed and the gummy substance is washed with ether. The substance is dissolved in 5 ml of water and applied to 150 ml of HP-20 resin and eluted with water. Fractions (30 ml each) 16-34 are combined and lyophilized to give 201 mg of the title compound as a solid.

Analysis: C 15 H 14 O 6 N 5 S 2 Cl 2 / 2H 2 O: Calculated: C 36.73 H 3.49 N 14.28 S 13.07 K 7.97 Found: C 36.65 H 3.00 N 13.99 S 13.48 K 8 Example 43. (i) - (cis, Z) -3 - [[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-oxo-4- (2- phenylethenyl) -1-azetidinesulfonic acid, potassium salt A solution of 68 mg of (Z) -2-amino-α- (methoxyimino) -4-thiazoleacetic acid and 51 mg of N-hydroxybenzotriazole monohydrate in 2 ml of dimethylformamide is treated with 69 mg dicyclohexylcarbodiimide. The mixture is stirred at room temperature for 30 minutes under nitrogen. (cis) -3-amino-2-oxo-4- (2-phenylethenyl) -1-azetidinesulfonic acid (90 mg) and 34 mg of triethylamine are added and the mixture is stirred for 20 hours under nitrogen. The slurry is evaporated in vacuo and triturated with 10 ml of acetone. The slurry is filtered and the filtrate is treated with 113 mg of potassium perfluorobutanesulfonate. Dilution with 30 ml of ether and filtration gives 169 mg of a solid product, which is dissolved in a small amount of about 10% acetonitrile / water and applied to 34 ml of HP -20 resin and eluted with 150 ml of water, then 10% acetone / water. Fractions (15 ml each) 16-19 are combined and freed from solvent to give 10 mg of the title compound as a solid.

C 17 H 16 O 6 N 5 S 2 K · H 2 O: Calculated: C 40.23 H 3.57 N 13.80 S 12.63 K 7.70 Found: C 40.03 H 3.05 N 13.61 S 12.31 K 7.56 Analysis: Example 44. (cis) -3 - [[2-amino-4-thiazolyl) [[1- (diphenylmethoxycarbonyl) -1-methylethoxy] imino] acetyl] amino] -4- (methoxycarbonyl) -2-oxo- 1-azetidinesulfonic acid, potassium salt A solution of N-hydroxybenzotriazole hydrate (34 mg) and 10 mg of 2-amino-α - [[1- (diphenylmethoxycarbonyl) -1-methylethoxy] imino] -4-thiazoleacetic acid in 0.5 ml of dimethylformamide is treated with solid dicyclohexylcarbodiimide (45 mg) and the mixture is stirred under argon for 45 minutes (room temperature). (cis) -3-amino-4- - (methoxycarbonyl) -Z-phoxo-1-azetidinesulfonic acid (45 mg; compare Example 188) is then added as a solid followed by triethylamine (0.03 ml) dropwise. The reaction mixture is stirred at room temperature for about 16 hours. The dimethylformamide is removed under high vacuum at 30 ° C and the residue is triturated with acetone. The supernatant is treated with potassium perfluorobutanesulfonate (67 mg). Dilution with ether gives a solid which is washed with ether and dried in vacuo to give 93 mg of the title compound.

Example Gel 45. (cis) -3 - [[(2-amino-4-thiazolyl) [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -4- (methoxycarbonyl) -2-oxo-1- azetidinesulfonic acid, dipotassium salt A slurry of (cis) -3 - [[2-amino-4-thiazolyl) - [[1- (diphenylmethoxycarbonyl) -1-methylethoxy) -imino] acetyl] amino] -4- ( methoxycarbonyl) -2-oxo-1-azetidinesulfonic acid, potassium salt in 0.4 ml of anisole is stirred at -12 ° C under argon and 0.9 ml of cold (-10 ° C) trifluoroacetic acid is added. After 1.5 hours, 4 ml of ether and 2 ml of hexane are added and the resulting slurry is stirred for 15 minutes at -10 ° C and then for 15 minutes at room temperature. The solid is isolated by centrifugation and washed with ether. The pH of the suspension of this material in 0.5 ml of cold water is adjusted to pH 6 with 1N potassium hydroxide A and then a 30 ml HP-20AG column is applied. Elution with water gives 30 mg of the title compound after evaporation (acetonitrile is added and evaporated twice).

Analysis: C 14 H 15 K 2 N 5 O 9 S 2: Calculated: C 31.15 H 2.81 N 12.98 Found: C 29.08 H 3.03 N 12.19 Example 46. [35- [3a (Z), 4ß]] - 3- [[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -4-ethynyl-2-oxo-1-azetidinesulfonic acid, potassium salt (Z) -2-amino-d- (methoxyimino) -4-thiazoleacetic acid (100 mg), 85 mg of N-hydroxybenzotriazole monohydrate and 113 mg of dicyclohexylcarbodiimide were weighed into a 10 ml flask. The flask was purged with nitrogen and cooled on an ice / water bath. Then 0.6 ml of dimethylformamide is added and the mixture is stirred for 10 minutes, at which time an additional 0.6 ml of dimethylformamide is added. 500 216 '61 (S) - (trans) -3-amino-4-ethynyl-2-oxo-1-azetidinesulfonic acid (95 mg) is added in solid form with 1.0 ml of dimethylformamide and 56 ml of triethylamine. The cold bath is removed and the mixture is stirred for 22 hours. Acetone (3 ml) is added and the solids present are removed by filtration and washed with a further 4 ml of acetone.

All solvents are removed in vacuo and the residue is taken up in 5 ml of methanol and 162 mg of potassium perfluorobutanesulfonate are added and dissolved. After storage, a solid is deposited which is then isolated by centrifugation to give 68 mg of the title compound, melting point,> 230 ° C.

Example 47. [3s (a) Js- [1- (2-amino-4-thiazolyl) [[[3 - [(z-furanylmethylene) amino] -2-oxo-1-imidazolidinyl] carbonyl] amino] acetyl] amino] - 2-oxo-1-azetidinesulfonic acid, potassium salt In the manner described in Example 6, but using (R) -2-amino-α - [[[3 - [(2-furanylmethylene) amino] -2- oxo-1-imidazolidinyl] carbonyl] amino] -4-thiazoleacetic acid instead of aminothiazoleacetic acid the title compound is obtained with a melting point> 250 ° C. Biological activity The following methods were used to determine the minimum inhibitory concentration (hereinafter referred to as MIC) for the β-lactams of the invention.

The test organisms are cultured in approximately 15-20 ml "Antibiotic Assay broth" (Difco) by inoculating (in tubes) the liquid with a loop amount of the organism from a "BHI" (Difco) oblique days.

The inoculated tubes are incubated at 37 ° C for 18-20 hours; These cultures are assumed to contain 109 colony forming units (hereinafter referred to as CFU) per ml. The cultures are diluted to 100: 100 to obtain a final inoculum content of 10 CFU; the dilutions are made with K-10 culture broth (defined below).

The compounds are dissolved in a suitable solvent at a concentration of 100 .mu.g / ml. Duplicate dilutions are made in K-10 culture broth to obtain a range from 100 μg / ml to 0.5 μg / ml. 1.5 ml of each dilution is introduced into individual square petri dishes, to which is added 13.5 ml of K-10 agar (defined below). The final drug concentration in agar varies from 100 .mu.g / ml to 0.05 .mu.g / ml. Organism growth control plates containing only agar are prepared and inoculated before and after the test plates. The organisms are applied to the agar surface of each plate with a Denley Multipoint Inoculator (which gives approximately 0.001 ml of each organism) resulting in a final inoculum content of 10 4 CFU on the agar surface.

The plates are incubated at 37 ° C for 18 hours and MIC values are determined. MIC is the lowest concentration of compound that inhibits the growth of the organism.

K-10 culture broth is a yeast / meat-containing culture broth containing: meat extract 1.5 g yeast extract 3.0 g peptone 6.0 g dextrose 1.0 g distilled water q.s. ad l liter 500 216 63 K-10 agar has the following composition: meat extract 1.5 g yeast extract 3.0 g peptone 6.0 g dextrose 1.0 g agar 15.0 g distilled water q.s. ad l liters The tables below indicate results obtained when the β-lactams according to the invention were tested against different organisms. The number given after each organism is the number of organisms in the collection of E.R. Squibb & Sons, Inc., Princeton, New Jersey. A dash (-) in the table indicates that the test compound does not show activity against the particular organism at 10 g / ml. The symbol "N.T;" indicates that testing has not been performed. 500 216 64 oo fi .I om oo fi m.N fi oo fi om oo fi om mw mN m.NH mw m. ~ HH fi mmñmxm um fl acw ux fl woum ||| Wl |: __ <e .Ugâ mmmæ ~ w: uw «mumomNwo.àßoßmo fl wrwuw mmmæ. mmßm æ f mm æßoo fi mmmæ mvvæ mm fifi w fi vm mßvæ mmmm ßmmm owvoa momo fi wmmo fi ßmæo fi vmmæ mmww ßmmm H fi if mw f o f oovw mmmm wßm al _ ßuøs fi mzxwu wmrošo fi zonm _smo: ¶m: Lwu wsrosonzwmm _W: mumwoLQE uw fi øzzmw .ww¶ :: mL% amwuuæozwwu ~ wo: umQLuc xcuucæoxu fi RAE. a @ ucQ ~ u Lu fl uuæmzmwzm _ wwrzow cNNæm «: w _umoa & m« uNNm: oENcm _w »Lum ~ z = mzuwozm __Lmm @@ uL nzmwosm _wwNw @ uLwE mzwgoxm _ wu¶: 9êu _N: m @ nn N <_wNou ßwxuwzmxunm _wNou uwxuwzwawmm __Nou uwcowaufuwæ __Nou Uwcuwzusunm _W: QQ: N æ: bUQmaLu «2 _muw @ uuNsmc mxououoßmua f w _N» Ncuuua mzuoouowmmaww _ wzwazu w: ououoNm: mw_w _ wzuazc m oooooN>: uc @ w _ wzmazø æzouomoN>: m: @n _ uzuxzu w: uoouoN>: QzQw Ew fl cmsuo 500 216 65 O lo O r-iv-l Il om com mm m.mH mm mH mm ~ mm ~ mm mm om om mm mm mm ~ I !! Lñ ßßæ fi æl-INGNHOI-ÜOQVÉI-lä fi l fi Q I O V V | o - ~ of «c> o <: v1o <: c> o <: c> o <: c> orn fi wocw P1 m.mH mm mm I mv l fi f fi f fi OII NUDW-D P4 Hmmšwxw um flfl cm uxsøoum ^ He \ m = V. uHz -_. | _n Pl vi ov L fi kßwqæ® IO 'Or-4I-IOÛr- (ÖOCDOCDÖOOOÖP1OICÛIN 1-1 V o U-'ICÜFÜ' “0q \ o \ ø fi mmmw ~ w: owQuoUouNco xuwuuao fl wzmmoo mmm mv mv mv mmmæ mwvæ mm flfi m f vm mßvæ mmmm ßmmm owvo al momo fi mmmol al ßmæo fi vmmæ mmvm ßæmm fifi about mm f o f oovm mmmm MSSM fi. .mnozwmsawu qßwczwmxxms mozowšwxwum wuzosowzwwm «n muumozuE uw al waamw .w @ w :: MA% Læ al muaox al mu ~ m @: @ msxwu amuuceoawmzm ~ wauao ~ u amumcaomu al zm .wæzsow cN ~ wm @: w Jvwoanmß S Nwzcëm um .nwxommxa WZM al OXM qwaumuuma MZW fi mxu .wwN »QøLmE wzwüøzm ~ wOM: o &: u: m ummwwnawwx .cezæcøgmu ummmwuaumx .NNQQ .MNOQ ~ mNou. @ NQO .nzu FL ZW uwxumxmanwm cwxuwzcsbum Hfæxümšusïvwm HJZTUMLQQQQM wzuuouczuwz .wm @ .Üc cum n = mu @ ospuu; @ ¿. v .wwmaoæøk nzuoououauauw .nzuxzc wzuuooommamßßw .nzmzzc uzuuouommcncün .nzuaxø uzvuouo m arg N qnzmzzu lcwm om. IOUJLÛ n EDIWæ®®®®®GBCKDODæ® $ PW.. Oo fi oo fi m.NH m.mH mN ~ Hwmâmxw um flfl cw uxswoum Mmmm .w: UW @ wucooNmn & 8uuQo @ u «o <mmmm mvmm mæßm arms æßoo fi wmwæ mvwæ mm fifl w fi vm mßwæ mmæm ßmmm ovvo al MOMO al wmmo fi ßmæo fi vmmm mmvm ßmmm flfi about mw f O fl oovm mmmm MSSM fi .mnozwczawu wczsëowzuna ~ cuo: ¶m = Lwu wwzosowzwum ~ w: u @ mwuLus cw fi nxamm .fi sëzugs .Sååå .G «ææ: cm © Lud x @ fl uuQo & m fi: c .mcouoNu Lwuouaszwßzm .wuszoq cN ~ um»: w @ cn Nu: @m. umzøwwzs w: w @@ ß & .wxmu fifi ma wzwusam «wwNwQuzwE wzwumzm ~ møw: oï: w: m @ ~ Nu @ mQuNx .wmzumoßwu cN ~ u» wa @ ~ x. »Nsu uwxuwzucønm ~ @ Nsu uwa nq ~ NNoo øwxmwzwcuqm ~ w: u »: N mxomouunuwä .ww ~ QuuNømm wsuuouoümuzüm fi ww fl uowßæ w: uoouo @ LwL @ m .mzwzzw w: uoomoNmxam§n ~ ɧšcwzounuuuuu99. u: uuouoN>: Lv @ u Em fl cmvuo 500 216 67 O lf! m.N fi - - | c> l fi PI v-l r-l v-l r-lv-i vlñl fl f fi llïr-dtñ fl ïf fi ætñø-lf fiflfi m I U .ONNQNCWNWWCNCWWNON IDO NO o-I m. ~ H m. ~ fi m oo fl | A.m about æ.o H.m æ.o m. ~ H m.H. mw mo om æ.o mm No _ Hm mo.ov æ.o Ho mH mo.ov mo mo.ov wH .mo.ov wH vo mm Ho w. fi æ.o ~ .m No wH eo m.NH mN ~ .m m.NH vo 1 mm | oo fi | mm | mw I m. ~ H w ß Hmmëwxm wm fifl cw uxøwoum ^ HE \: _ .UH2 Mmmm ~ m: om »muuouNuu am fl usßo fi wzwow mmmæ mwmm mæßm m fi mm æßoo fl wmmæ mvwæ mm flfi o v mm ß mm ß mm. wßw fi Äšßzwmsxmß møsoâowzmmm qcwozwmzxos wuzosowsmum .wzwuwæuaus sw fi caxwm .wwwzzmxk xw al ucæoauwu qmmzwmoxmu aw al nuæozwurw .wcouoNu mu al uu @ oæu «m .wuzzon u ~ NWM @: w .uwoxmm fi uNNw: oENum« mæsømN's mxwuoam fïwmß al ma wzšoxm ~ nwNwQuLwE mzmwozm .ucwzoäxmzm developing wwmQ @ ~ m .w @: mm9 ~ mc cNNo¶m @ uNx «w ~ zn wwxuwàmcuwm ~ ¶Nou cwxowzmaznm ~ ¶Nou uwxuwmuxmnm .wNoo cwxowzmawnw ~ w: u @: N wzouooozuwt« wuw @ os ~ cmm uu. % wzooouo fl mmaüm | w: ma: uw: oooooN>: @ u @ m .nxzzzn mzuuooowmcmcüw ~ w: mL: ß w: oooocNmfmcNw .nzuzws n: uoøusNn Em fl cmmuo 5Û0 216 68 c \ DI \ 1 \ D \ D ~ 1 \ D \ {\ 1 DPCf-I® \ Ov- | . . r-IIWFIPÄNDGfÛÖI-ÄCFÜOI-í flfi f fi L fifl ïf fi oo n fl n ('\ J \ O \ D (\ JO r-'l fi wmimxm um flfl cw uxsøoum ^ ~ e \ m =. .uHz MMM m qmwïuwu m uwUm uUUm m UUGU m UUGUN. @ -æ mqvm mm flfl w fl qm øßww mmm »> ~ mm ovvo fi momo fi wmmo fl ßmwo fi« m ~ @ m @ «~ ~ @ ~ m fifi cm mw fi o fi o °« ~ QQMN wßw fl qcwoswmzamu mmsosowzwmwwwwwwww. Lw @ uunøx @ ¶u .wwzmmozmw aeuuuaozuuzm »fëcnß Nm Ltwïuïænitü: m .wwzzom u ~ Nwm @@ m ~ uwoxmm @ mN ~ w: oENum .wwLmmN :: mzw fl oxm ~ ¶Lm www; mnwwm awmm. .wmzwmoamc uN ~ www @ m ~ x ~ »Noo øwxuwawanwm« wNoo cmxowamaumm ~ »~ oo uwxowawaowm .w ~ oo cwxo¶Lw: owm ~ w: w @: N wzouoooxuwä .wo fi wuuwumc wzouoooumwaum wmouwm ~ ma. = uuøuoNmxmc »w fi wzwazu m: uooooNm: ms fl m« w: uL: ß mzuoouommxmuuw .wzuazu mzuuoooNmxmø ~ w Em fl cmmuo 500 216 V 69 a nu fi | OO | IIDO CO PJÖP4Ö-IV- {F-ÖÖ Ö4-ÖF-Ö-IV-I-IV- IC \ I in! | - | I-ív-lv-l u-lv-llfïæl- fi \ ß oo oouj coa rl ri in \ D \ Df'1® \ D L fi rl Q 'ø-i CWIWFIWNOCNGNrÄNWHOOCWU ~ D | | | mmmæqmsuw fi wucmø fl mu Lm fi uu ooßmsvuw om oo fi | mmmæ .cnozwlæ fi um mësoëovzwwm. m m. w mm m v m m .swošmš mc wusosowzwum om m.w m. ~. fi mæßm .wswuwuuxcë u fi zäxwm mm m. if . m fi m fi mm .wwwrzmås .ÉÉUQQLQUNQ. H m. æßOO .m wwn.ti._l_ñ _._ m.š _ ~ _w «. \ .: š ~ m _ .. ~ .. \, .. WßN. o m.m m. NH mmmæ. ~. ~ \ Q ~ .¿_Ns. ~ u «uc, .._... ï, ...,: m .a m.o m.NH mvwæ .wuzzom uNNumw: w. o N. o .H. m m mona .mmoamwñ UN N mšoïMcw .o N.o H.o m fi vo .uwfšmwza mxw fi ßzm .ov ~ .o N.o mßwæ ... Éuo fi mx wzuoozn .o v.o m.o mmæm qmušoouzwo: wššoza m. m oo wo. .n mw mm "ovvo fi .wmzæmozmu SNS wouï .o o fifl H. m momo fl ... Sao uÉuozÉowm .m mo m. ~ H omæo fi. @ NSvcw: m? ë¿uwm .H wA mH ßmæo fi_ .oooo uwxooauovmm .A m .Na m. ~ H vmmæ .wïäuswauïïšmwm mN v. O oo mmvm .wzw fi ß wzuuooszuwä .No w. Fl am ßæwm .mø @% ouNcuc wzmuoooümwzum | mm | H | , oo wN .nznšzs nzcmouøo nagon om m. Na m N m mmm .wzwxzc wzuuouoomxmu fi m.. om mN mm www H Jšwazu wzuuøuoïocncum ma NA HA Em fl cæmpo Hmmšwxw um fifi cw uxs mw. m ~ m ~ mm WN m. ~ H WN m ~ V @ .H m. ~ H mm m ~ m. ~ H m. ~ H... | _n | fqQQQQQF-q fi wfñfñfñßl F fi v-íø-'Åv-l Hgpspq -k al WO (WNONNWO oa 0 Ü OMHHOHO Ln N Hwmawxw pm fifi aw ßiøøoum ^ ~ e \ m =, .uHz m. ~ f oo al oo f Mmmm .wxuw al moßocwwu Lm fi uceo fi wzwæw mmmw mvmm mæßm æ f mm æßoo fi wmwæ mvvæ mm fifi w fi vm aßvm mmæm ßmmm ovvo fi momo al wmæo fi ßmæo al vmwæ mmvm ßæmm a fi om mw fi o fl oovm mmmm wßma ~ uoo: ww: Lwc nC: Q? nw: wnm .cwuzwmzzmu wczoïowzæwß ~ w: æmnæma fl E mwuczzum ~ ¶¶N :: mL% Lm »ws;, QL @ NQ; _ ~ L \ «« + «;; t, @ .acf rthu LzF: ß @ m; ç.¿m .wwrzow uNNmwNaw ~ uwo Ãwwzcmwzs w: u fl «; @ .vñšswmx Éwšnšw quwwwpdxwï o: u @ s; A .auwso fi äwzn øN ~ m» wN uN xw. .MNQU swsuwamcuw. .wNoo øwxmwzusuum «@Noo øwaowzæsumm .NNQU üwsvwzmawwm ~ wz @ Q: N nzmoouwzuwä ~ wnw @ nvMøuc wzuuoucüuazwn .owxwcæcæ w: uuouo fl Lu; @u .o: w; ~ w: n; sn: uuooQNmxmu @ m fl nzuazu m: uooooNmaaU fl n .æ: u; zm w: ouoooNm: Lu @ m Ew fl cmvuo 500 216 71 oo fi Hm oo fi oo fi ooa oN Hmmšwxw um fi acw uxøwoum mw mmv mm mm m. ßmmm ovvo fi momo al wmmo fi ßmæo fi vmmm mmem ßwmm fifi if mw fl o f oovm mmmm wßm fi .m: UW @ muuooNuu Lm fi uunouwnwuw .uwozwmzamu muzoëowzmmm .umozwmzawc wuzosowxmmm qmzmomuo FI SE umuuß fi MW .wwwzzmax awuuunoagwu .wæzmmoaæu & m «Quaoamu: m ~ wuouoNm aw al ounoamuam qwmrzom developing mm» @w .wmoxmmu u§Nm = o = acm .mwaumN = a mzmuosm .wswm fl uwa mzu fi ogm .mwN¶QmLwE mzwuonm qwuvmoszuzm uN ~ mwmnmNx .mwzmmoawc øN ~ wmmau ~ x «w ~ ou uwxowàmwm xm @ xwwowx ~ x. w: m «: N m = uoouo & u»: .muw »ooNumu mzouououmwa fl m .m @ Nøuøß \ wzouooo fl mwa fi m .wzmzzu w = nuooo ~ m: mu» w .wzwazo w: uuooo ~ mxmu »w qmzoo flmzwazo nz. 72 fl wmáwxw um flfi cw vxswou m ^ He \ m = v .uHz mmmm mmmm mwmm mmßm æ fi mm æboo fi mmmm mwwm mm fifl w fl vm mßwæ mmmm ßmmm ovwo fi momo fl mmæo fi ßmæo fl vmmm mmww ßmmm H fl om mw fl o fi ooww fl oww L oww L oww m oww L oww m oww m oww m oww m ~ uwo: »m: awu, mm: oEo¶: wmm qmzmuwwuams uwøøsnmm qwßwzzwax Lwuuunoßuwu .mwswmoxwu Lwwouaoamuzm ~ mcucoNu Lmøocaoamuzw qwwzzom cN ~ mmwxm Jëzomåm m m ~ a. wawzoszwzm u-mwmau ~ x qmwzwmoawc cNNw »onm ~ M« @Nou uwcumnmxomm «wNoo uwxownmxomm ~ @ Nou cwmumamæomm q fifi ou uwxomkmaoem .wz @»: ~ wzouoooaowz .uuwuouNouuuu muuu wu. ~ m .mzwazu w: ououo ~ mxm «w .wzwzzu mzuuouc fl mxmuum Em fi cmmuo 500- 216 73 oo Ö COOOOOll-ñ NNQNQ-w I OI mo.ov mo.ov mo.ov mo.ov l fl I-IfWÖIÖfVFÛOO-Ü O PCWWOOÖOOG V oø fi co fi vw l fi v-lmf-i æv-iæ fl 'Ö fi <' \ D @ I-lv- {f'1f'1 I .. .Ö o44ç> møw \ øu1 | O o V o O 0 d o - I lu1ø <fi c «w <: v1dc: c> c Fe lill 'mm Hwmëxm um flfi cw uxsøoum ^ ~ s \ m =. .uHz mmmæ mmmæ mvmm mmßm arms mßoo fi wmmm MVVM mm flfl w fi vm mßvæ mmæm ßmmm ovvo al momo fi wmæo al ßmæo fi vmmm mmvm ßmmm A fi if mw f o f oovm mmmw wßw fi 4. .mzow al muuouwuu Lm al muno al mzwow .cmozwmzamc qcmozwmzamu mu fi ëääšmmm wuaèäëšwmm .mzmummuaus uw fi uaamu .w »w: = ua% amuucnoauwu qmmzmmoamc am fi uunoam fi zm ~ mcouoNo zm fi oonoawuzm ~ ¶w: = om uN ~ wm »xm .uwoxmwß 3 Nwzøšom .w¶Lum ~ = a æaw fl oam ~ .Éwm fl Q wa mzw fl oå .w¶w fl nw wm ~ x maw wxm ~ Nwwønm ~ M ~ wNou. ~ NQu .QNQQ .wN @@ ~ m: m fl: N uwæuwxwæomm uwxumswxumm umxowamæomm umxomamxomm mxooouoaowæ .wuw »uuNømu mzuooooßmmaum ~ mwNuuwcM mzuwamm oo ^ m. Q = ooouo ~ mxmu @ m åššušägåšää Em fl cmmuo BUU 216 74 0 G90 ¶F7F1 l fl f fi wwf fi Ido l OI \ D \ ONU1 | Or-4U10 \ D \ D '| CQ \ O | -iv - {\ D FIM !!! oou @ 1-1 \ DN Awmämxm um flfl cm uxøwoum ^ He \ m = v .uHz Mmmm mmmm mvmm mmßm æ fl mm æßoo fi wmmæ mvvm mm fifl w fi vm mßvæ mmmm ßmmm ovvo fl momo fl wmwo fi ßmæo mm mm m ow mmm H mmm fi mmm ov mmm ov mmm ov mmm sm fi uunoumzwow qumozwmzzmu ~ umo: wm: Lmo Eëošäšmßw wuzoso fi zmmm .m: @ommuacE uwußnàmm .www fl: ua% Ämubüâgu. Mb .wmzmmozmu Lm fi usaoawunm q wuumoN u z fi uußoa fi: m .wwzzom u ~ Nmmw; m .swoxmš SN wcošsw ~ mæaumN = a mamuonm qwnwmu fi ma mzmuoam ~ wwN ~ @ saws mxwuwmm xwwmm. .¶Nou «wNou .w: @@ z ~ uwxowamxumm owxowamxuww uwxowsmxomm uwxuwawxomm mzuooooauwt« @cw fi uuNsmu mzuuooo al mwxum mwNuuwu ~ \ m_Eooooumma »m -wzwzzu m onouoNmxßu» w .mzwzxm m uuouo ~ mxmuum qmzmxxc m uuouoNm: muum qmzmzzu wzuuooogmxmuum Em fi cmmuø 500 216 75 om I fl. M oo fl ~ »m mw mw ooa Hm ooa Hm mm Hm m.mH mw m. ~ Fi vo æ.o Hm m.NH mw mw mw oo fi mH mm Hm mm HA .tm mw om oo fl 1 m.N fi | Nm Hm fi wmäwxw um flfi cm uxøwoum Of-If-imw-Nvw. u ulf; c> O <3c> oc3c> Of4N r-iv-l om .He \ m = v .uH: Mmmm mwmæ mvmm mmßm mama æßoo fl wmmæ mvvm mm flfi w fi vm mßvæ mmæm ßmmm owwo fi momo fi wmæo fi ßmæo fl mmm fi wmmm H mmmm fl wmmm æ o »» mououNuo aw al ußeo al æzwuw .unozwmzamø muzosä fi zmmm .umozwmzzwu wuzoso fi zuwm .mzwuwwoass owuøaaæm qw al wzzmaæ am fi ouaenuwo .wwzwmoawu microns al uunoau al ZM ~ mumuoNu am fi uuaoauuzm .wwzzow u »mm: w šwoäwß SN wzošum .m @ aumN: = mzmuonm .wawm fi uwa mzwuonm .fi âêgws MSAA ~ moo »: OE = m = mu ~ Nw» waw ~ x .wwzwmoßwu cN ~ @ wm @ m ~ x «w ~ oo uwxumamxomm .QNQQ uwxuwamxomm .wNou cwaowamxowm .QNQQ uwxowauxomm .n: w ~: N nzuooooauwz. @ U-uuN. wzuoouo @ tting »m ~ mwNsowsM wzuuoooumwaum qwzmxzc w: uuouo ~ mxmuum .nxwzzs = zuuoooNm & UO« m .nzuxzc u ocouoNmxmu «m .mzmxzc mzuuouo fi mxmcum Ewwcmmuo 500 216 76 f f f f r LVT fi æwN flfi NNF fiflfi f f r lv ICW ooo @@ | \ D \ O \ 'ÛONOr-4000 © O \ D \ D \ OF) 0W \ Dl- fi l fl oo mw m.NH mw vn Hwmšøxw um flfl cm uxswoum ...: Mmmm mwmm mvmm mæßm æ fl mm mßoo fl wmmæ mevæ mm fifi w fi vm mßmm fi wmm mmvm ßæmm H fi om mm fl o fi oowm mmmm wßm fi ~ m: uw »mououNco Læ fi uüaoumz Wow. wa mzæuonm .w @ N @ auL @ E mzmuonm qwswzosxwzm u ~ Nm @ maæ ~ x .mmsmmoawø uN ~ m @ mam ~ æ .Son uvxuwæmxuøm. »~ oo cwxumswxowm .MNQQ uwzumswxomm .¶Noo zwwzwoo fl. uu ~ ømc wzouoooummaum .m »Nmuws% wzouoooßmwsum qmzumzc w: muooo ~ mxmu ~ m .m: uL: u mzooßuoNm & mUuw .wzmzzu nzooouoNmxmuum .wzwszu wzomouoámcmucm

Claims (9)

500 216 77 PATENT REQUIREMENTS 1. l. Ss-Lactam of the formula HIW R 2 34 R -Na-E - Ö-'R3 1 6 Û 00; N 3 is characterized in that R 2 is hydrogen or alkoxy having 1-4 carbon atoms; R 3 and R 4 are the same or different and each represents hydrogen or alkyl or one of R 3 and R 4 is hydrogen and the other is alkoxycarbonyl, alken-1-yl, alkyn-1-yl, cycloalkyl, phenyl, optionally with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, lower alkyl or lower alkoxy groups substituted phenyl, 2-phenylethyl or 2-phenylethynyl; M + is hydrogen or a cation, with the proviso that when both R and R 3 are R 2 is the 2-amino-4-thiazolacyl group of the formula: is hydrogen, R is not hydrogen or methoxy; and wherein R 13 is hydrogen, alkyl, cycloalkyl, alkylaminocarbonyl, ON -C-NH-R 11 or alkyl substituted with one or more halogen, cyano, nitro-, amino-mercapto-, alkylthio-, R 11-, carboxyl-, carboxyl-salt , amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl or dialkoxyphosphinyl substituents, wherein R 11 is phenyl, optionally with nitro and substituents . Β-Lactam according to Claim 1, characterized in that it is a salt of | 3S- | 3u (Z), 4ß || -3- || (2-amino-4-thiazolyl) (methoxyimino) acetyl | amino] -4-methyl-2-oxo-1-azetidinesulfonic acid. 3. β-Lactam according to claim 1, characterized in that it is a salt of | 3S- | 3d (Z), 4ß || -3- ||| (carboxymethoxy) imino | (2-amino-4 -thiazolyl) acetyl [amino] -4-methyl-2-oxo-1-azetidinesulfonic acid. 4. β-Lactam according to claim 1, characterized in that it is a salt of 13S- | 3 $ (Z), 4ß || -3- || (2-amino-4-thiazolyl) I (1-carboxy -1-methylethoxy) iminolacetylamino] -4-methyl-2-oxo-1-azetidinesulfonic acid. Β-Lactam according to claim 1, characterized in that it is a salt of | 3S- | 3dJZ), 4ß || -3- || (2-amino-4-thiazolyl) | (1-carboxyl-1 -methylethoxy) iminolacetyl [amino] -4-methyl-2-oxo-1-azetidinesulfonic acid, dipotassium salt. Β-Lactam according to Claim 1, characterized in that it is a salt of β-β-3 (Z), 4-di-3 "|| (2-amino-4-thiazolyl) methoxyimino) acetylamino] -4-methyl -2-oxo-1-azetidine-sulfonic acid. Β-Lactam according to Claim 1, characterized in that it is a salt of β-S-I3 (Z), 4-1-3- || (2-amino-4-thiazolyl) | (1-carboxy- 1-methylethoxy) imino [acetyl] amino] -4-methyl-2-oxo-1-azetidinesulfonic acid. 8. | 3S- | 3 (Z), 4ß-I-3- || (2-amino-4-thiazolyl) | (1-carboxy-1-methylethoxy) iminolacetylamino] -4-methyl-2-oxo-1- azetidine sulfonic acid. 500 216 79 Β-Lactam according to claim 1, characterized in that one of R 3 and R 4 is methyl and the other is hydrogen and that R 13 in the group R 1 is an alkyl group having a carboxyl substituent as defined in claim 1, wherein R 13 determined is an isopropyl group having a carboxyl substituent on the central carbon atom, so that the β-lactam has the formula: S11 H cn H3N: L§N / \ EjLlP -: - 1/3 \ o