LU85033A1 - AZETIDINYL-SULFONIC ACID AND ITS ANALOGS - Google Patents

Description

"

Azetidinyl sulfonic acid and its analogs "

The present invention relates to a new family of β-lactam antibiotics, as well as the use of these compounds as antibacterial agents. It has been discovered that the β-lactam nucleus can be activated biologically by a substituent corresponding to Rr R, *. 5 \ / 6 to the formula -0-C-S0 „H (or a salt thereof) fixed at

O

the nitrogen atom of the nucleus.

10 ß-lactams having a substituent

Rr Rr S \ / 6 -0-C-S0-H (or a pharmaceutically acceptable salt thereof

O

tables) in position 1 and an acylamino substituent in position 3 exert activity against a range of 15 gram-negative and gram-positive bacteria.

Among the members of the new family of ß-lactams antibiotics of the present invention, there are, for example, those corresponding to the formula: = 2 = 4

20 RrNH-Ç - Ç-R3 R5x H

/ C_N - 0 - C - SO.H

^ 30 or one of their esters or their salts.

As used in Formula I and throughout this specification, symbols have the following definitions:

Rn is an acyl group; A * R2 is a hydrogen atom or a group. methoxy j R. and R. are the same or different and 3 4 each represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group or a tetragonal, pentagonal, hexagonal or heptagonal heterocycle (hereinafter referred to as R ^) L ~ i + U * '1 | j 2 or one of the radicals R ^ and R ^ is a hydrogen atom and the another is an azido group, a halomethyl group, a dihalomethyl group, a trihalomethyl group, an alkoxycarbonyl group, a 2-phenylethenyl group, a 2-phenylethynyl group, a carboxy group, wine group a -SX ^ group, a group - OX ^ j a group X3 X3 0 -OCX ^ y a group -SCX ^ or a group —A — C-NX ^ X ^ i

V * S

X ^ is an azido group, an amino group (-NH ^) * a hydroxy group, an alkanoylamino group, an alkylsulfonyloxy group, a phenylsulfonyloxy group, a (substituted phenyl) sulfonyloxy group, a phenyl group, a substituted phenyl group, a cyano group,

15 a group -S-X2 or a group -O-X2 J

X2 is an alkyl group, a substituted alkyl group, a phenyl group, a substituted phenyl group, a phenylalkyl group, an (substituted phenyl) alkyl group, an alkanoyl group, a substituted alkanoyl group, a phenylcarbonyl group, a (phenyl substituted) carbonyl or a hetero-arylcarbonyl group; one of the radicals X ^ and X ^ is a hydrogen atom and the other is a hydrogen atom or an alkyl group or, X ^ and X ^, taken together with the carbon atom to which they are attached , form a cycloalkyl group}

Xj. represents a formyl group, an alkanoyl group, a phenylcarbonyl group, a (substituted phenyl) carbonyl group, a phenylalkylcarbonyl group, a (substituted phenyl) alkylcarbonyl group, a carboxy group, an alkoxycarbonyl group, a group 10 11 aminocarbonyl (KH ^ -C-), a (substituted amino) car-bonyl group or a cyano group (-C = N)}

L

it 3 A represents a group -CH = CH-, a group -CH2-CH = CH-, a group - (CH ^,) - ^, a group - (ΟΗ ^^, - Ο-, a group - (CH2 ) n, -NH-, or a group - (CH2) n, -S-CH2; n is equal to 80,1,2 or 3 J 5 n 'is equal to 1 or 2; ": Λ and X ^ are identical or different and each represents a hydrogen atom or an alkyl group or X ^ represents a hydrogen atom and X ^ represents an amino group, a substituted amino group, an acylamino group or an alkoxy group j and

Rj. and are the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a cycloalkyl group or R ^, or alternatively R ^ and R ^ , taken together with the carbon atom to which they are attached, represent a cycloalkyl group or R ^, or one of the radicals Rj. and R ^ is a hydrogen atom and the other is an azido group, a halomethyl group, a dihalo-methyl group, a trihalomethyl group, an alkoxycarbonyl group, a 2-phenylethenyl group, a 2-phenylethynyl group , a carboxy group, a group -CI ^ X ^, 0

II

a group -S-X2, a group -0-X2, or a group -A-C-NX ^ X ^, Definitions of various terms used to describe the β-lactams of the present invention will be given below. These definitions apply λ, to these terms when these are used throughout. throughout this specification (unless they are otherwise limited in specific cases) either individually or as part of a larger group.

The terms "alkyl group" and "alkoxy group" refer to straight chain groups and branched chain groups. Among these groups, those

L

4 containing 1 to 10 carbon atoms are preferred.

The terms "cycloalkyl group" and "cycloalkenyl group" denote cycloalkyl and cycloalkenyl groups containing 3j 4> 5j 6 or 75 carbon atoms.

The term "substituted alkyl group" 3. denotes alkyl groups substituted by one or more substituents selected from an azido group, an amino group (-NH ^), a halogen atom, a hydroxy group, a carboxy group , a cyano group, an alkoxycarbonyl group, an aminocarbonyl group, an alkanoyloxy group, an alkoxy group, a phenyloxy group, an oxy (substituted phenyl) group, an R ^ -oxy group, a mercapto group, an alkylthio group, phenyl-15 thio, a (substituted phenyl) thio group, an alkylsulfinyl group or an alkylsulfonyl group.

The terms "alkanoyl group", "alkenyl group" and "alkynyl group" refer to straight chain groups and branched chain groups.

Among these groups, those containing 2 to 10 carbon atoms are preferred ·

The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine.

The term "protected carboxy group" means a carboxy group which has been esterified with a conventional acid protecting group. These groups are well known in the art (see, for example, U.S. Patent No. 4,144,333 granted March 13, 1979) Preferred protected carboxy groups are esters benzyl, benzhydrylic, t-butylic, and p-nitrobenzyl.

"Substituted phenyl group" means a phenyl group substituted by 1, 2 or 3 substituents selected from an amino group (—NE 4) * a halogen atom, a hydroxy group, a tri-1 group. fluoromethyl, an alkyl group (containing 1 to 4 carbon atoms), an alkoxy group (containing 1 to 4 carbon atoms) or a carboxy group.

The expression "tetragonal, pen-tagonal, hexagonal or heptagonal heterocycle" (designated by "R ^") denotes aromatic and non-aromatic groups ;; substituted and unsubstituted containing one or more nitrogen, oxygen or Among the substituents there is, for example, an oxo group (= 0), a halogen atom, a hydroxy group, a nitro group, an amino group, a cyano group, a trifluoromethyl group , an alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms, an alkylsulfonyl group, a phenyl group, a substituted phenyl group, a 2-furylimino group, CH = N- (1 _______ H) i a benzylimino group and a substituted alkyl group (the alkyl group containing 1 to 4 20 carbon atoms). A type of "tetragonal, pentagonal, hexagonal or heptagonal heterocycle" is the group "hetero-aryl" The expression “hetero-aryl group” designates the tetragonal, pentagonal, hexagonal or heptagonal heterocycles which are t aromatic. Among hetero-aryl groups there are, for example, (substituted and unsubstituted) groups pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl , thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl and tetrazolyl.

Among the non-aromatic heterocycles (i.e. fully or partially saturated heterocyclic groups) there are, for example, the groups (substituted and unsubstituted) azetinyl, oxetanvl, thi-tanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl,; 2-oxo-1-imidazolidinyl, 5 3-alkylsulfonyl-2-oxo-1-imidazolidinyl, 3-benzylimino- 2-oxo-1-imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl, 3-phenyl- ( or substituted phenyl) -2-oxo-1-imidazolidinyl, 3-benzyl-2-oxo-1-imidazolidinyl, 3- (2-aminoethyl) -2— oxo-1-imidazolidinyl, 3 “amino-2-oxo-1 -imidazolidinyl, 3- 3- [(alkoxycarbonyl) amino] -2-oxo-1-imidazolidinyl, 3- [2- [(alkoxycarbonyl) -amino] ethyl] -2 — oxo-1-imidazoli-dinyl, 2-oxo- l-pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4- hyd roxy-6-methyl-2-pyrimidinyl, 2-oxo-1-hexahydro-azepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-furanyl, 15 2,3-dioxo-1-piperazinyl, 2.5 -dioxo-1-piperazinyl, 4-alkyl-2,3-dioxo-1-piperazinyl and 4 ~ phenyl-2,3-dioxo-1-piperazinyl.

The expression "substituted amino group" designates a group corresponding to the formula —NY ^ Y2 in which Y ^ is a hydrogen atom, an alkyl group, a phenyl group, a substituted phenyl group, a phenylalkyl group, or a (substituted phenyl) - alkyl group and Y2 is an alkyl group., a phenyl group, a substituted phenyl group, a phenylalkyl group, an ((substituted phenyl) alkyl group, a hydroxy group, a cyano group, an alkoxy group , a phenylalkoxy group or an amino group (-NH2).

The term "substituted alkanoyl group" includes within its scope compounds of the formula (substituted alkyl) -C- (where the term "substituted alkyl group" has the meaning defined above) and a group phenylalkanoyl.

The term "acyl group" denotes all organic radicals deriving from an organic acid L ·) 7 (ie a carboxylic acid) by elimination of the hydroxy group. Of course, certain acyl groups are preferred, but this preference should not be considered as a limitation on the scope of the present invention. Among the acyl groups, there are, for example, those which have been used in the past to acylate β-lactam antibiotics, especially 6-aminopenicillanic acid and its derivatives, as well as 7-aminocephalosporanic acid and its derivatives 10 (see, for example, "Cephalosporins and Penicillins”, edited by Flynn, Academie Press (1972), patent application of the Federal Republic of Germany DE-OS 2,716,677 published on October 10, 1978, the patent Belgian 867 * 994 published on December 11, 1978, the patents of the 15 United States of America n ° 4 * 152,432 granted on May 1, 1979, 3,971,778 granted on July 27, 1976 and 4 * 172,199 granted on October 23, 1979, same as British Patent I.348.894 published March 27, 1974) The parts of these references which describe different acyl groups are referred to here for reference. The following list of acyl groups is given to illustrate further the expression "acyl group" ·, it should not be considered as a limiting list this expression. Among the acyl groups there are, for example: (a) the aliphatic groups corresponding to the formula: 0 - Il ‘· Ra-C- 30 in which R is an alkyl group, a cy- 3 group.

cloalkyl, an alkoxy group, an alkenyl group, a cycloalkenyl group, a cyclohexadienyl group, or an alkyl group or an alkenyl group substituted by one or more substituents chosen from a halogen atom, a cyano group, a nitro group, a * ! amino group, mercapto group, alkylthio group or cyanomethylthio group.

(b) Carbocyclic aromatic groups corresponding to the formulas:

R

rc- e

Rc 15

Rb ~ ^ T ^ _ ^ C ^ "R'd" Y y-s-ch2-c- or

where n is equal to 0, 1, 2 or 3 j R ^, Rc and R ^ represent each independently of one another, a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, an amino group, a cyano group, a trifluoromethyl group, an alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms or an aminomethyl group \ and R

L

i 9 is an amino group, a hydroxy group, a carboxy salt, a protected carboxy group, a formyloxy group, a sulfo salt, a sulfo-amino salt, an azido group, a halogen atom, a hydrazino group, a group 5-alkyl hydrazino, a phenylhydrazino group or a [(alkylthio) thioxomethyljthio group.

Preferred carbocyclic aromatic acyl groups include those of the formulas: HO-M-CH2-C- Q_c „21 15 ^ CH2NH2 HO - (/ 'S-CH-C- (R represents,

VZz / R

e preferably a carboxy salt or a sulfo salt) and 20 y-v 0 // V CH-C- (R represents,

\ = J R

e preferably a carboxy salt or a sulfo salt) · (c) The heteroaromatic groups corresponding to the formulas: 0 R £ - (cH2) n-C- 0 R.-CH-C- i 0

Rf-0-CH2-C- 0 *. R „-S-CH9-C- Λ 10

0 0 Il II

Rf — CC- where n is 0, 1, 2 or 3 l R has the meaning defined above and R ^ represents a 5-membered hetero-cyclic ring 5, 6 or 6, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Among the heterocyclic rings, there are, for example, the thienyl, furyl, pyrrolyl, pyri-dinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidi-nyl, thiadiazolyl and tetrazolyl rings. Among the substituents are, for example, a halogen atom, a hydroxy group, a nitro group, an amino group, a protected amino group, a cyano group, a trifluoromethyl group, an alkyl group containing 1 with 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms or a group ------- 0 H00C-CH-CHo-0-C-NH-.

1 ^ 20 NH2

Preferred heteroaromatic acyl groups include those of the "above formulas in which R 4 is a 2-amino-4 * -thiazolyl group, a 2-amino-5-halo-4-thiazolyl group, a group 4 -25 aminopyrimidin-2-yl, a 5-amino-1,2,4-thia-diazol-3-yl group, a 2-thienyl group, a 2-fura-nyl group or a 6-aminopyridin-2- group yle.

(d) The [[(4-substituted-2,3-dioxo-1-piperazinyl) carbonyl] amino] arylacetyl groups corresponding to the formula: 0 0 / - \

II / \ -C-CH-NH-C-N N-R,

H

0 0

/ L

/ v— ft 11 in which R is an aromatic group (including carbocyclic aromatic hydrocarbons such as those corresponding to the formula:

R

· 5 and heteroaromatic hydrocarbons falling within the scope of the definition of R ^); and R ^ is an alkyl group, a substituted alkyl group (the alkyl group is substituted by one or more substituents selected from a halogen atom, a cyano group, a nitro group, an amino group or a mercapto group), an arylmethylene group -amino (i.e. a group 15 -N = CH — R where R has the meaning defined above), ë ë an arylcarbonylamino group (i.e. a group 0

II

-NH-CR where R has the meaning defined above) ë ë or an alkylcarbonyland.no group · 20 Among the preferred [[(4-substituted-2,3-dioxo-piperazinyl) carbonyl] amino] arylacetyl groups , there are those in which R ^ is an ethyl group, a phenylmethylene-amino group or a 2-furyl-methylene-amino group.

(E) The (substituted oxyimino) aryl-acetyl groups corresponding to the formula: 0 —C-ON-O-R.

I 1

R

ë in which R has the meaning defined above ë and R ^ is a hydrogen atom, Rc, an alkyl group, a cycloalkyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group (i.e. a group 0! l 35 -C-NH-R where R has the meaning defined above) or ë ë

L

12 a substituted alkyl group (the alkyl group is substituted by one or more substituents chosen from a halogen atom, a cyano group, a nitro group, an amino group, a mercapto group, an alkylthio group, an aromatic group (such as defined by R), a carboxy group (including its salts), a g group, amido, an alkoxycarbonyl group, a phenylmethoxycarbonyl group, a diphenylmethoxycarbonyl group, a hydroxyalkoxyphosphinyl group, a 10-dihydroxyphosphinyl group, a hydroxy group (phenylmethoxy) phos-phinyl or a dialkoxyphosphinyl group).

Preferred (substituted oxyimino) arylacetyl groups include those in which R is a 2-aminO-4-thiazolyl group. Also preferred are groups in which R ^ is a methyl group, an ethyl group, a carboxymethyl group, a 1-carboxy-1-methylethyl group, a 2,2,2-trifluorethyl group or a 1- group. carboxycyclopropyle.

(f) The (acylamino) arylacetyl groups corresponding to the formula: 0 0

1! II

-C-CH-NH-C-R.

. J

R

g in which R has the meaning defined above

S

25 and R. represents a group J

i \ (CH ^) —0-, amino group, alkylamino group, (cyano-alkyl) -amino group, amido group, alkylamido group, (cyanoalkyl) group - NH r, - \

• 11 // V

amido, a group -CH2-NH-C r 'N, a group

U

é 13 nh 0

»Z II

• -CH-CH2-C-NH-CH, a group W- “S02-N (CH2-CH2-0H) 2, a group

OH

HO OH

Va -e \\ - ch, 1X11 erouPe K IJ I j

10 W

OH

a group ^ .. / - 0 \ N / \ n 15 II I N N-CH, or t_ / _ ^ 0 a group HO y | | ho — NykAc-.

Λ ‘lî 20 0 0

Preferred (acylamino) arylacetyl groups of the above formula include those in which R. is an amino group or an amido group. Are

"J

Also preferred are groups in which R is a phenyl group or a 2-thienyl group.

(g) The [[[3 ~ substituted-2-oxo-1-imidazolidinyl] carbonyl] amino] arylacetyl groups corresponding to the formula: 30 0 - Il 0 0 ^ c ^ -C-CH-NH-CN KR, "II ^ R CH0 CH„ g 2 2 wherein R has the meaning defined above at 35 and R ^ represents a hydrogen atom, an alkyl-sulfonyl group, an aryl-methylene-amino group (it is ie a group -N = CH-R where R has the meaning defined above (S ë 0 above), a group -C — R (where R is a hydrogen atom, an alkyl group or a alkyl group substituted by a halogen atom), an aromatic group (as defined by R above), an alkyl group or a substituted alkyl group (the alkyl group is substituted by one or more substituents chosen from an atom halogen, cyano group, nitro group, amino group or mercapto group).

Preferred [[[3-substituted-2-oxo-1-imidazo-lidinyl] carbonyl] amino] arylacetyl groups of the above formula include those in which R 1 is a phenyl group or a 2-thienyl group. Also preferred are groups in which is a hydrogen atom, a methylsulfonyl group, a phe-nylmethylene-amino group or a 2-furylmethylene-amino group.

The terms "salt" and "salts" refer to basic salts formed with inorganic and organic bases. These salts include ammonium salts, alkali metal salts such as sodium and potassium salts (which are preferred) , alkaline earth metal salts such as calcium and magnesium salts, salts formed with organic bases, for example, cicyclohexylamine salt, benza-thine, N-methyl-D-glucamine salts , hydrabamine, as well as the salts formed with amino acids such as arginine, lysine and the like. Non-toxic and pharmaceutically acceptable salts are preferred, although other salts are also useful, for example, to isolate or purify the product.

The salts are formed in the usual way by reacting -the product in the form of a free acid with one or more equivalents cb the base ap—

L

t 15 propriée providing the desired cation in a solvent or a medium in which the salt is insoluble, or in water and removing the water by lyophilization. By neutralizing the salt with an insoluble acid such as a cation exchange resin in the hydrogen form (for example, a polystyrene-tallow acid resin such as the "Dowex 50" resin) or with an aqueous acid and by extraction with an organic solvent, for example, ethyl acetate, dichlorome-10 thane or the like, the form of free acid can be obtained and another salt can optionally be formed.

Ss-lactams having a substituent

Rc ra '5 \ / o -OC-SO ^ H (or one of its salts) in position 1 and a subset 15 amino or acylamino in position 3 contain at least one chiral center - the carbon atom (in posi - _____tion 3 of the ß-lactam nucleus) to which the amino or acylamino substitute is attached. The present invention relates to the β-lactams which have been described above and in which the stereochemistry on the chiral center at position 3 of the β-lactam nucleus is the same as the configuration existing on the carbon atom at position 6 of naturally obtained penicillins (eg, penicillin G) and the configuration existing on the carbon atom at position 7 of naturally obtained cephamycins (eg, cephamycin C).

With regard to the preferred β-lactams of formula I, the structural formulas have been given to illustrate the stereochemistry existing at the chiral center in position 3 ·

Racemic mixtures containing the β-lactams described above also fall within the scope of the present invention.

16 "

Ss-lactams having a VA, -OC-SO ^ H substituent (or a salt thereof) in position 1 of the ß-lactam nucleus and an acylamino substituent in position 3 of the ß-lactam nucleus exert activity against a range of gram-negative and gram-positive organisms,

Rr RA

5/6

The substituent -O-C-SO ^ H (or a salt thereof) is essential for the activity of the compounds of the present invention.

The compounds of the present invention can be used as agents for combating bacterial infections (especially urinary and respiratory tract infections) in mammalian species such as pets (e.g. dogs, cats , cows, horses and the like), as well as in humans.

To combat bacterial infections in mammals, a compound of the present invention can be administered to a mammal in need of this compound, in an amount of from about 1.4 mg / kg / day to about 350 mg / kg / day preferably in an amount of from about 14 mg / kg / day to about 100 mg / kg / day, All of the modes of administration which have been adopted in the past for administering penicillins and cephalosporins at the site of 1 are also contemplated for the new family of β-lactams of the present invention. Among these modes of administration are oral administration, intravenous administration, intramuscular administration and suppository administration.

The β-lactams of the present invention can be prepared from an amino acid responsive to

/ V

17 darrt to the formula: OH v R, iO> 4

KH0-CH- C - R0 II

2, 3

/ C-OH

5 0 ^

The amino group is first of all protected by a conventional protective group (for example, a t-butoxycarbonyl group, a benzyloxycarbonyl group, an o-nitrophenylsulfenyl group, etc.), to obtain a compound corresponding to the formula: OH v R. tN \ x 4

A, -NH-CH- C - R, III

1 | 3

.C-OH

0 ^ 15 In formula III and throughout this specification, the symbol "A ^" denotes a nitrogen protecting group.

The carboxy group of a protected amino acid of formula III is then reacted with an amine 20 corresponding to the formula:

Rr ^ Λα (¾ 5 ^ Çs

NH ^ - 0 - C - S03W IV

The reaction takes place in the presence of a coupling agent such as l-ethyl-3- (3-d.imethyl-25-aminopropyl) ~ carbodiimide or dicyclohexylcarbodimimide and it gives a salt of a compound corresponding to the formula: OH XR,. i 4

A. -NH-CH- C - R- p V

30 1 I 3 VR6

/ C-NH-0 - C - S0_H

0 ^ 3

The hydroxy group of a compound of formula V (or a salt thereof) is transformed into a group which is removed using, for example, a conventional reagent such as methane sulfonyl chloride (the group

/ K

18 methane-sulfonyl is hereinafter referred to as "Ms")

The completely protected compound corresponding to the formula: OMs R. i 4

5 Α, -NH-CH- C — R9 p p VI

1 | 3 Çî Λ

_ KH - 0 - C - SO, H

0 ^ 3 or one of its salts is cyclized by treatment with a base, for example, potassium carbonate. Preferably, the reaction is carried out in an organic solvent such as acetone under reflux conditions and a compound of formula: * 4 is obtained.

Ai -NH-CH-C - R0 p p VII

15 1 I I 3 v5 / R6

Ä C _N - 0 - C - S0oH

3 or one of its salts.

Alternatively, one can cyclize a compound of formula V without first transforming the hydroxy group into a group that is moving away.

Treatment of a compound of formula V (or one of its salts) with triphenylphosphine and diethyl azodicarboxylate or carbon tetrachloride and tri-thylamine gives a compound of formula VII.

25 ~ The two methods described above for the cyclization of a compound of formula V give rise to the inversion of stereochemistry on the carbon atom linked to the substituents R ^ and R ^.

Deprotection of the 3-amino substituent of a compound of formula VII can be accomplished by adopting well known techniques. If, for example, the protecting group is a t-butoxycarbonyl group, trifluoroacetic acid can be used to deprotect the amino group. If the protecting group is a benzyloxycarbonyl group, catalytic L · 19 hydrogenation (eg, with palladium on carbon) can be used.

If the protecting group is an o-nitrophenyl sulfenyl group, p-toluene sulfonic acid can be used in combination with ρ-thiocresol. The deprotected compound k- 5 (or one of its salts) corresponds to the formula: = 4

NHo - ÇH-C - R

I | 3 ^ / 6

_N - 0 - C - SO.H VIII

0 ^ 3 10 and it is a key intermediate for the preparation of the compounds of the present invention. The compounds of formula VIII form an integral part of the present invention.

Well-known acylation techniques can be adopted to transform a compound of formula VIII into a corresponding compound (or one of its salts) corresponding to the formula: §4

R, - NH - CH-C - R. IX

By way of example, techniques such as reaction with a carboxylic acid (R 1 —OH) or with a carboxylic acid anhydride or a corresponding carboxylic acid halide will be mentioned. . Reactions with a carboxylic acid. most readily take place in the presence of a carbo-diimide such as dicyclohexylcarbodiimide, as well as in the presence of a substance capable of forming an in situ reactive intermediate such as

~ C

N-hydroxybenzotriazole or 4-dimethylaminopyridine, When the acyl group (R 1) contains reactive functionality (e.g. amino or carboxy groups), it may be necessary to protect these functional groups first and then carry out the acylation reaction and finally deprotect the product obtained ·

The products of formula X in which is a methoxy group can be prepared from the corresponding compound of formula VII in which is a benzyloxycarbonyl group. The halogenation ... (preferably chlorination) of the nitrogen atom of the amido group of a compound of formula VII (A ^ is a benzyloxycarbonyl group) gives a compound corresponding to the formula I / ΓΛ? ï1 § * W 2 i i 3

/ C-N - 0 - C - S0.H

0 ^ J

15 or one of its salts

Reagents and methods for the N-chlorination of amides are known in the art.

Reagents include, for example, tert-butyl hypochlorite, sodium hypochlorite and chlorine. The reaction can be carried out in an organic solvent (for example, a lower alkanol such as methanol) or in a two-phase solvent system (for example, a mixture of water and methylene chloride) in the presence of a base such as sodium borate to 10 molecules of water. Preferably, the reaction is carried out at a reduced temperature.

Reaction of a compound of formula X with a methoxylating agent, for example, an alkali metal methoxide, gives a compound (in combination with its enantiomer if and are the same or if X is a racemic mixture) corresponding to the formula: r — v 0 0CH3 g4

Vch2-0-c-nH-c- ^ -R3 Rj ^ XX

'-' .C_H - 0 ^ C- S0, H

35 0 ^ 3 /! // / _____ / 21 or one of its salts.

The reaction can be carried out in an organic solvent, for example, a polar organic solvent such as tetrahydrofuran, at a reduced temperature.

Alternatively, a compound of formula VII (in which is a benzyloxycarbonyl group) can be transformed into a compound of formula XI by adopting a one-step process. The methoxylating agent can first be mixed with a compound of formula VII (A ^ is a benzyloxycarbonyl group), while the N-chlorination reagent is then added to the reaction mixture.

The transformation of a compound of formula XI 15 into the desired products of formula I can be carried out by adopting the methods described above for the transformation of an intermediate product of formula VII into a product according to the present invention.

The starting materials of formula II can be readily obtained by adopting methods well known in the art (see, for example, "Synthesis", page 216 (1979) and "'J. Org. Chem." "44: 3967 (1979)).

The following examples illustrate specific embodiments of the present invention.

25 Example 1

[3S- [3α (Ζ), 4β]] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[4-methy1-2-oxo-1- (sulfomethoxy) -3 -azetidinylJ amino] - 2-oxoethylidenej amino oxy -2-methylpropanoic acid, dipotassium salt 30 A) Aminoxymethanesulfonic acid

1.46 g (20 millimoles) of acetone oxime was added to a suspension consisting of a dispersion of 60% mineral oil of 0.8 g (20 millimoles) of sodium hydride in 16 ml dry dimethyl sulfoxide.

35 We then added, in portions, 3 * 94 g (20 milli-

U

22 moles) of sodium bromomethane sulfonate. The reaction mixture was heated to 90-95 ° C for 4 hours under a nitrogen atmosphere, cooled and washed twice with 250 ml of ether. The solidified product was washed with 100 ml of dichloromethane, filtered and dried over To obtain 15.3 g of a crude material. The latter was dissolved in 20 ml of water and 7 * 5 g (22 millimoles) of tetrabutylammonium hydrogen sulfate were added.

The product obtained with paired ions was extracted twice with 200 ml of dichloromethane. The dichloromethane solution (Na ^ SO ^) was dried and concentrated in vacuo. The hydrolysis of acetone oxime was carried out by heating at 130 ° C for 4 hours in 120 ml of 2N HCl. This solution was concentrated in vacuo twice in water, then in acetonitrile.

The product solidified upon addition of dichloromethane, then it was filtered and dried in vacuo to give 2.5 g of the title compound.

B) O-sulfomethyl-qNt-butoxycarbonyl-L-threonine hydroxamate, potassium salt At a temperature of 0 ° C, 1.14 g (8.9 millimoles) of aminoxymethane-sulfonic acid was added to a solution of 1.96 g (8.9 millimoles) of t-butoxy-carbonyl-L-threonine in 16 ml of water and 4 ml of tetrahydrofuran. The pH was adjusted to 4 * 5 with Κ0Η IN. and 1.87 g (9 * 7 millimoles) of 1-ethyl ~ 3- (3-dimethylaminopropyl) -carbodiimide hydrochloride in 8 ml of water was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and, during this period, the pH was maintained between 4 and 4.5 with occasional addition of SO 2 IN, the ions were paired of the product with 3.05 g (8 millimoles) of tetrabutyl-ammo-35 ni um hydrogen sulfate at a pH of 2.8 and the aqueous solution was extracted with four 100 ml portions of dichloromethane . The dichloromethane solution (NaoS0.) Was dried and concentrated in vacuo to give 4.5 g of a product as the tetrabutyl-5-ammonium salt. The latter was transformed into potassium salt by ion exchange on 150 ml of "Dowex 50 X" (0.7 niéq K © / ml) and, after lyophilization, 2.63 g of the compound were obtained under , C) Hydroxamate e d10-sulfomethyl-gNt-butoxycarb onyl-L- 10 (O-methane-sulfonyl-threonine), tetrabutylammonium salt A partial solution of 2.37 g (6.5 millimoles) d1hydroxamate d10- sulfomethyl-αNt-butoxycarbonyl-L-threoninefsel from K "in 50 ml of dry pyridine at a temperature of 0-5 ° C. and under a nitrogen atmosphere, 0.8 ml was added dropwise (excess ) methane sulfonyl chloride. The reaction mixture was stirred at room temperature for 4 hours, then concentrated in vacuo. The residue 20 was dissolved in 10 ml of water and 2 g (6 millimoles) of tetrabutylammonium hydrogen sulfate at pH 2.8 was added. The material of which the ions were paired was extracted with chloroform. The chloroform was dried and concentrated in vacuo to give 2.6 g of a crude product, D) [3S- (3a, 4ß)] - 3 - [[(1,1-dimethylethoxy) - carbonyl] -amino -4-methyl-2 ~ oxo-l- (sulfomethoxy) —azetidine, potassium salt

2.6 g (4 millimoles) of hydro-xamate d * 0-sulfométhyΙ-α-Ν-t-butoxycarbonyl-L- (0- methane — sulfonyl — threonine), tetrabutyl ammonium salt, were dissolved in 5 ml of acetone and the solution obtained was added dropwise to a suspension (brought to reflux) of 2.2 g of potassium carbonate in 65 ml of acetone. The heating at reflux was continued for 3 *5 hours

U

24 and the reaction mixture was cooled, filtered and concentrated in vacuo * The residue was dissolved in 10 ml of KE ^ PO ^ 0.5M, pH 5.5 and the pH was adjusted at 2.8, the product was extracted four times with 100 ml portions of dichloromethane, then the combined extract was dried and concentrated in vacuo to give 1.52 g of the crude salt of ß- tetrabutyl ammonium paired lactam. The potassium salt was obtained by ion exchange through 50 ml of "Dowex 50 X" 10 (0.7 meq K® / ml) to obtain, during lyophilization, 0.53 g of a material crude which was further purified by chromatography through 100 ml of "HP-20" using water. The appropriate fractions were combined and lyophilized to obtain 0.245 g of the product.

Analysis: for C1 () H1 ^ N20 ^ SK.1,2 H20:

Calculated; C 32.46; H 5.28; N 7.57 J S 8.66 Found: C 32.52; H 4.76; N 7.43} S 8.30.

E) [3S- (3oc, 4ß)] -1-sulfomethyl-3-amino-4 “methyl-2-oxo-20 1-azetidine

We put 0.245 g (0.68 millimole) of [3S- (3α, 4ß)] - 3 - [[(1,1-dimethylethoxy) carbonyl] amino] -4-methyl-2-oxo-l- (sulfomethoxy ) -azetidine, potassium salt, suspended in 0.5 ml of dichloromethane and 0.5 ml of anisole. “The reaction mixture was cooled to 0 ° C and 1 ml of trifluoroacetic acid was added under a nitrogen atmosphere. The reaction mixture was stirred for one hour, then concentrated in vacuo to obtain a residue which was evaporated twice in benzene. This residue was then triturated with ether, then the ether was decanted to obtain the desired product as a white solid.

l · 25 F) [3S- [3a (z), 4ß]] acid “2 - [[[l- (2-amino-4-thiazolyl) -2- [[4.-methyl-2-oxo-l - (tallow omethoxy) -3-azetidinyl] ~ amino] -2-oxoethylideneJ amino j oxy j —2-methylpropionic, diphenylmethyl ester, potassium salt 5 0.30 g (0.68 millimole) of was dissolved (Z) -2 — amino-a- [[2- (diphenylmethoxy) —1,1-dimethyl-2-oxoethoxy] imino] -4-thiazole-acetic acid and 0.10 g (0.68 millimole) 1-hydroxybenzotriazole hydrate in 4 ml of dry dimethylformamide under a nitrogen atmosphere · 10 This solution was cooled to 0 ° C and 0.14 S (0.68 millimole) of Ν was added in portions , Ν'-dicy-clohexylcarbodiimide. At the end of the addition, the reaction mixture was stirred at 0 ° C for one hour.

To this was added a solution of the crude 3-amino-1- (sulfo-methoxy) -azetidine above (about 0.68 millimole) in 10 ml of dimethylformamide and 0.5 ml of Ν, oprop-diisopropylethylamine at 0 ° C, The reaction mixture was stirred at 0 ° C for one hour, then at room temperature overnight. The solution was filtered and the filtrate was concentrated in vacuo.

The residue was dissolved in 50 ml of dichloromethane and washed with 2 ml of water. Upon evaporation of the dichloromethane, 0.372 g of a crude product was obtained. The latter was passed through 30 ml of 25 - 'Oowex 50 "(0.7 meq K ® / ml) using water to obtain, during lyophilization, 0.211 g of a crude product contaminated with hydroxybenzotriazole, G) Acid [3S- [3a (Z), 4ß]] “2 - [[[l- (2 ~ amino-4-thiazolyl) -2— [[4-methyl-2-oxo ~ l - (sulfomethoxy) -3-azetidinyl] - 30 amino] -2-oxoethylidene] amino] oxyJ-2-methyl-propanoi'que, dipotassium salt r 0.211 g of [3S- [3cc (Z ), 4β]] - 2- [[[1- (2-amino-4-thiazolyl) - 2- [[4-methyl-2-oxo-l- (sulfomethoxy) -3-az.étidinyl] amino] - 2-oxoethylidene] -35 amino] oxy] -2-methylpropionic acid, diphenylmethyl ester Λ 26 that, potassium salt, in 1.8 ml of dichloromethane, 0.5 ml of anisole and 1.5 ml of trifluoroacetic acid and stirred under a nitrogen atmosphere at 0 ° C for 2 hours · The reaction mixture was concentrated in vacuo and evaporated twice in benzene ·

The residue was washed with a 1: 1 mixture of ether and ethyl acetate, as well as with a 1: 1 mixture of ether and acetonitrile to obtain a white solid. The latter was dissolved in 1 ml of KH ^ PO ^ 0.5M, pH 5j5j the pH was adjusted to 6.5 with IN KOH and chromatography was carried out through 40 ml of HP-20 with water to obtain 53 mg of compound under heading a melting point of 200 ° C (decomposition). Analysis: for C ^^ H ^ yN ^ 0 ^ S2K2 * 2.75 H ^ O 15 Calculated: c 28.44 5 H 3.84 d N 11.85 "S 10.84

Found: C 28.32; H 3.36; N 11.90; S 10.37.

Example 2

[2S- [2a, 3ß (Z)]] - [[3 - [[(2-amino-4-thiazolyl) - (methoxyimino) acetyljaminoJ-2-methyl-4 “Oxo-l-azéti-2 0 diny1 oxy] methane-sulfonic

Following the method of Example 1 and substituting an equimolar amount of (2) -2-amino-a - [(methoxy) -imino] —4 ~ thiazole-acetic acid for the thiazole-acetic acid used in part (F) of Example 25, the compound under heading is prepared in the form of the monopotassium salt (hygroscopic solid) after dissolution in acetonitrile and after having removed the acetonitrile several times under vacuum. of infrared rays - SO ^ 30 (1030 cm "1); ß-lactam (1778 cm-1)

Analysis: for Cj ^ H ^^ N ^ O ^ S2K.O, ÎCH ^ CN Calculated: C 38.11; H 4.82; N 15.92; S 12.56 Found: c 37.94 1 H 5.36; N 15.92; S 12.56.

/ L

27

Example 3 - Acid [2S- [2a ^ 3ß (R-)]] - [[3— [[[[((4 — ethyl — 2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl] amino] - 2-met hyl-4-oxo-1-azetidinyl] oxÿ} -methane-sulfonic 5 Following the method of 1 * example 1 and substituting 1 * oc- [[(4-ethyl-2,3-dioxo- 1-piperazinyl) -carbonyl] amino] -phenylacetic with thiazole-acetic acid used in part (F) of Example 1, the compound is obtained in the form of the monopotassium salt (hygroscopic solid) "Infrared ray absorption spectrum - SO ^" "(1038 cm ~ ^); ß-lactam (1775 cm * "*)

Analysis: for C2qH2 ^ N ^ 0 ^ SK.1,6H2O Calculated: C 41.53 5 H 4.74. N 12.11; S 5.54 15 Found · c 41.53 S H 4.46 3 N 11.13 3 S 5.61.

Example 4 (S) -3-b enzyloxycarbonylamino-4 ~ methyl-2-oxo-l- (tallow o-methoxy) -azetidine

Following the method of Example 1, parts 20 (A) to (D), and substituting the benzyloxycarbonyl-serine for the t-butoxycarbonyl-L-threonine used in part (b), the compound is prepared under heading in the form of a potassium salt; infrared ray absorption spectrum - SO ^ "" (1025 cm "**) 5 25 ß-lactam (1775 cm" "*).

By following the methods described above, the following compounds are prepared: (3S-trans) - | ~ [(2-amino-4 ~ thiazolyl) - (methoxyimino) acetyl] amino] -4-methyl 1-2- oxo-1-azetidinyl] -30 oxy] methane-sulfonic, 3 "monopotassium salt ü> (3S-trans) acid - [[(2-amino-4-thiazolyl) - [(2,2,2 —trif luor ethoxy) imino] ac etyl] amino] —4 — methyl-2— oxo-l-azetidinyl] oxy] methane-sulfonic, monopotassium salt 3

U

28 (3S-trans) acid - [[(2-amino-4-thiazolyl) - [(2-amino-2-oxoethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinyl ] oxy] methane-sulfonic, mono-potassium salt; 5 (3S-trans) - [[(2-amino-4-thiazolyl) - [(carboxymethoxy) imino] acetyl] amino] -4-niethyl-2-oxo-1-azetidinyl] -oxy] methane- sulfonic, dipotassium salt; 1 (3S-trans) acid - [[(2-amino-4-thiazolyl) - [[(1-carboxy-cyclopropyl) oxy] imino] acetyl] amino] -4-10 'methyl-2-oxo-1 -azetidinyl] -oxy] methane sulfonic acid, dipotassium salt $ [3S- [3oc (R), 4ß]] - [[3 - [(aminophenyl acetyl) amino] —4-methyl-2-oxo- l-azetidinyl] oxy] methane-sulfonic, monopotassium salt; (3S-trans) - [[3 - [(phenylacetyl) amino] - 4-methyl-2-oxo-1-azetidinyl] oxy] methane-sulfur, monopotassium salt with acid (3S-trans ) - [[3 - [(2-thienylacetyl) - amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methane-tallow o-20, monopotassium salt $ acid (3S-trans) - [[3 ~ [(2,6-dimethoxy-phenyl) acetyl] amino] -4-methyl-2-oxo-l-azetidinyl] oxy] -methane — sulfonic, monopotassium salt $ 1'acid [3S- [3ß ( R)> 4ß]] ~ [[3 - [[[[(aminocarbo-25 nyl) amino] -2-thienylacetyl-amino] -4-methyl-2-oxo-1-azetidinyl] -oxy] -methane-sulfonic acid , monopotassium salt; , [3S- [3a (R), 4ß]] - [[3 - [(carboxyphenylacetyl) amino] —4-methyl-2-oxo-1-azetidinyl] oxy] methane— 'sulfonic acid, salt dipotassium; [3S- [3a (+), 4ß]] - [[3 - [(phenylsulfoacetyl) amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methane-sulfon acid, salt dipotassium; (3S-trans) acid - [[3 “[[((2-amino-4-thia-zolyl) -oxoacetyl] amino] -4-methyl-2-oxo-1 -azetidinyl] - 35 oxy] methane- sulfonic, monopotassium salt to 29 1 * acid [3S- [3a (R), 4ß]] - [[3 - [[[[[[2-oxo-3 - [(phenyl-methylene) amino] -1-imidazolidinyl ] carbonyl] -amino] phenylacetyl] amino] - 4 ~ methyl — 2-oxo— 1-azetidinyl] - oxy] methane-sulfonic, monopotassium salt; LS acid [3S- [3a (Z), 4ß]] - [[3 - [[2-furanyl- (methoxyimino) acetyl] amino] -4-methyl1-2 — oxo-1-azetidi— nyl] oxy ] methane sulfonic acid, monopotassium salt $ 3S (Z) acid - - [[3 “[[((2-amino-4-thiazolyl) - • (methoxyimino) acetyl] amino] -2-oxo-l-azetidinyl ] oxy] - methane-sulfonic, monopotassium salt; [3S (Z)] - [[3 - [[(2-amino-4-thiazolyl) - [(1-carboxy-1-methylethoxy) imino] acetyl] amino] -2-oxo-1-azetidinyl acid ] oxy] methanesulfonic, dipotassium salt $ [3S (Z)] acid - - [[3 - [[(2-amino-4-thiazolyl) -15 [(2,2,2-trifluorethoxy) imino] acetyl ] amino] -2-oxo-1-azetidinyl] oxyjmethane-sulfonic, monopotassium salt; 1 [3S (Z)] acid - [[3 - [[(2-amino-4 “'thiazolyl) - [(2-amino-2-oxoethoxy) imino] acetyl] amino] -2-oxo-l— azetidinyl] oxy] methane sulfonic acid, monopotassium salt with [3S- [3a (S), 4ß]] acid - - [[3 - [[[((aminocarbonyl) amino] -2 -2-thienylacety1] amino] - 2-oxo-1-a zetidinyl] -oxy] -methane-sulfonic, monopotassium salt with [3S- [3a (+) i4ß]] acid - [[3 - [(phenylsulfo-acetyl) amino] -2- oxo-1-azetidinyl] oxy] methane-sulfoni-25 ", dipotassium salt; acid [3S- [3a (R), 4ß]] - [[3 - [[[[(4-ethyl-, 2 , 3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl] - amino] -2-oxo-1-azetidinyl] oxy] methanesulfonic acid, salt U- · monopotassium; [(3S (Z)] acid - [[3 “[(phenoxyacetyl) amino] - 2- oxo-l-azetidinyl] oxy] methane-sulfonic, mono-potassium salt; (3S-cis) acid - [[(2-amino-4-thiazolyl ) - (methoxyimino) acetyl] amino] -4-methyl1-2-oxo-1-azetidinyl] -35 oxy] methane sulfonic acid, monopotassium salt;

L

(3S-cis) -ff (2-amino-4-thiazolyl) - [(2,2,2-trifluoroethoxy) imino] acetyl] amino] -4-methyl- 2-oxo-1-azetidinyl acid ] oxy] methane-sulfonic, mono-potassium salt; ^ 5 (3S-cis) acid - [[(2-amino-4-thiazolyl) - [(carboxy-methoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methane-sulfonic acid, dipotassium salt with (3S-cis) acid - [[3 - [[(2-amino-4-thiazo-lyl)] - (1-carboxy-1-methylethoxy) imino] acetyl] amino] -2-10 oxo-4-methyl-1-azetidinyl] oxy] methane-sulfonic acid, dipotassium salt $ (3S-cis) acid - [[(2-ajnino-4- "thiazolyl) - [[(l- carboxy-cyclopropyl) oxy] imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methane-sulfonic, dipotassium salt; (3S-cis) acid - [[(2-amino -4-thiazolyl) - [(2-amino — 2-oxoethoxy) imino] acetyl] amino] —4 — methyl — 2— oxo-1-azetidinyl] oxy] methane-sulfonic, monopotassium salt $ 20 [3S acid - [3a (R)> 4a]] - [[3 - [(carboxyphenylacetyl) amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methane-tallow, dipotassium salt} acid [3S- [3a (R), 4a]} - [[3 - [[[[((4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl] -2 5 amino] -4- methy 1-2 -oxo -1 -a zét i diny 1] oxy] methan e-sulf o - nique, monopotassium salt;, acid [3 S- [3a (S), 4a]] - [[3 - [[[((aminocarbonyl) amino) -2-thienylacetyl] amino] -4-methyl-2-oxo — 1-azetidinyl] oxy] methane- sulfonic, monopotassium salt; [3S- [3a (R), 4oc]] - [[3 - [(an »inophenylacetyl) —amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methan e- sulfonic, monopotassium salt.

AT

;

Claims (4)

1. I3V / 6 / C-N - 0 - C - SO.H 15 0 ^ 3 or one of its salts or esters, formula in which R ^ is an acyl group; R2 is a hydrogen atom or a methoxy group $ R ^ and R ^ are the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a phenyl group , a substituted phe-nyl group, or a tetragonal, pentagonal, hexagonal or heptagonal heterocycle, or one of the radicals R ^. and R ^ is a hydrogen atom and the other is an azido group, a halomethyl group, a dihalomethyl group, * a trihalomethyl group, an alkoxycarbonyl group, a 2-phenylethenyl group, a 2-phenylethynyl group, a group carboxy, a group -CH2-X ^, a group -S-X2, 3 hr a group -0-X „, a group -0-CX, a group -SCX. Δ T 4 t 4 XS X5 L 33 Ο 11 or a group -A-C-NX ^ X ^; R ^, R ^, X ^, JL ^ f A, X ^ and X ^ have the meanings defined in claim 1 and one of the radicals X3 and X ^ is a hydrogen atom and the other is a d atom hydrogen or an alkyl group or X ^ and X ^, taken together with the carbon atom to which they are attached, form a cycloalkyl group X X is a> formyl group, an alkanoyl group, a phenylcarbonyl group , a (substituted phenyl) carbonyl group, a phenylalkylcarbonyl group, a (substituted phenyl) al-kylcarbonyl group, a carboxy group, an alkoxycarbonyl group, an aminocarbonyl group, an (substituted amino) carbonyl group or a cyano group. 4 · ß-lactam according to claim 3, characterized in that R2 is a hydrogen atom. 5. ß-lactam according to claim 4 * characterized in that one of the radicals R- and R. is 3 4 different from hydrogen. 6. ß-lactam according to claim 4 3 characterized in that R ^ is a hydrogen atom and R ^ is a methyl group. 7 · ß-lactam according to claim 4> characterized in that R ^ is a methyl group and R ^ 25 is a hydrogen atom. 8. ß-lactam according to claim 4 * "characterized in that R ^ and R ^ each represent a hydrogen atom. * 9 · ß-lactam according to claim 4 »30 characterized in that R ^ and each represent a methyl group. 10. ß-lactam according to claim 4 "characterized in that is a group (z) -2-amino-oc- [(1 -carboxy-1-methyl-ethoxy) imino] -4-thiazole-acetyl. 34 11 · ß-lactam according to claim 3 * characterized in that R ^ j R ^ and R ^ each represent a hydrogen atom, while one of the radicals and is an alkyl group and the other is a d atom 'hy-S drogenic. 12. ß-lactam according to claim 3 * characterized in that R £ j R ^ j R ^ and R ^ each represent a hydrogen atom and R ^ is a methyl group. * 13 · ß-lactam according to claim 3j 10 characterized in that R £, R ^, R, - and R ^ each represent a hydrogen atom and R ^ is a methyl group. 14 · ß-lactam corresponding to the formula: = 4 15 NH9-CH-C-R, _ _ 2. I 3 V / R6 -N - 0 - C - S0-H Cr ^ or a salt thereof, formula in which R ^ and R ^ are identical or different and each represents a hydrogen atom, an alkyl group, a group alkenyl, an alkynyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group or a tetragonal pentagonal, hexagonal or heptagonal heterocycle, or one of the radicals R ^ and R ^ is a hydrogen atom and the another is an azido group, a halomethyl group, a dihalomethyl group, a trihalomethyl group, an alkoxycarbonyl group, a 2-phenylethenyl group, a carboxy group, a —CI ^ X ^ s group —S —X £, a group 30 n * 3? 3 -O-Xn> a group -0-CX ,, a group -SCX, or an i 4 , 4 X5 X5 0 t! group -AC-NX ^ X ^ y 35 Rg and are the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a phenyl group, a substituted phenyl group, a cycloalkyl group or a tetragonal, pentagonal, hexagonal or heptagonal heterocycle, or R, - and R ^, together with _ the carbon atom to which they are attached, represent a cycloalkyl group or a tetragonal, j pentagonal, hexagonal or heptagonal heterocycle, or alternatively one of the radicals R ^ and R ^ is a hydrogen atom and the other is an azido group, a halomethyl group, a dihalomethyl group, a trihalomethyl group, an alkoxycarbonyl group, an alkenyl group, an alkynyl group, a group 2-phenylethenyl, a 2-phenylethynyl group, a carboxy group, a group C1-X2, a group -S-X2, O II a group -0-X2 or a group -AC-NX ^ X ^; Xj is an azido group, an amino group, a hydroxy group, an alkanoylamino group, an alkylsulfonyloxy group, a phenylsulfonyloxy group, a (substituted phenyl) sulfonyloxy group, a phenyl group, a substituted phenyl group, a cyano group, a group -S — X2 or a group -OX ^ 3 X2 is an alkyl group, a substituted alkyl group, a phenyl group, a substituted phenyl group, a phenylalkyl group, an (substituted phenyl) alkyl group, an alkanoyl group , a substituted alkanoyl group, a phenylcarbonyl group, a (substituted phenyl) carbonyl group or a heteroarylcarbonyl group; one of the radicals X „and X. is a hydrogen atom and the other is a hydrogen atom or an alkyl group, or also X ^ and X ^, taken together with the carbon atom to which they are attached, form a cycloalkyl group T represents a formyl group, an alkanoyl group, a phenylcarbonyl group, a (substituted phenyl) carbonyl group, a phenylalkylcarbonyl group, a (substituted phenyl) alkylcarbonyl group , an S carboxy group, an alkoxycarbonyl group, an aminocarbonyl group, a (substituted amino) carbonyl group 1 or a cyano group 3 A represents a group -CH = CH-, a group s -CH2-CH = CH-, a group - (CH2) n-, a group - (CH2) n, -0-, 10 a group - (CH2) nI-NH-, a group - (CH2) n, -S-CH2- 5 n is equal to 0 , 1, 2 or 3 3 is equal to 1 or 2 3 and X ^ and Xy are the same or different and each represents a hydrogen atom or an alkyl group, or X ^ is a hydrogen atom and X ^ is an amino group, a substituted amino group, an acylamino group or an alkoxy, 15. ß-lactam group according to claim 1, namely a salt of the acid [3S- [3cc (Z), 4ß]] - 2 - [[[1- (2- 20 amino-4 -thiazolyl) -2 - [[4-methyl-2-oxo-1— (sulfomethoxy) - 3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2 ~ methyl-propanoic. 16. ß-lactam according to claim 14 *, namely [3S- (3a, 4ß)] - 1-sulfomethoxy-3-amino-4 ~ methyl-2-oxo-1-azetidine. VXJOooj