FR2534253A1 - AZETIDINYL SULFONIC ACID AND ANALOGS WITH THERAPEUTIC ACTION - Google Patents

Abstract

B-LACTAMES CARRYING A SUBSTITUTE (CF DRAWING IN BOPI) IN POSITION 1 AND AN ACYLAMINE SUBSTITUTE IN POSITION 3. THEY MEET THE FORMULA: (CF DRAWING IN BOPI) IN WHICH R IS A RADICAL ACYL, A HYDROGEN ATOM OR A A PROTECTIVE GROUP OF THE AMINE FUNCTION, R IS A HYDROGEN ATOM OR A RADICAL METHOXY, R, R, R AND R ARE THE SAME OR DIFFERENT AND ARE EACH, PREFERRED, A HYDROGEN ATOM OR A LOWER RADICAL ALKYL. THESE COMPOUNDS CAN BE USED AS ANTIBACTERIAL AGENTS.

Description

2534253 '

  The present invention relates to a new family of elactam antibiotics, as well as to the use of

  of these compounds as antibacterial agents.

  It has been discovered that the core of e-lactams can be activated biologically by a substituent of formula

R RR

-O-C-503H

  (or a salt thereof) attached to the nitrogen atom of the ring.

  C-lactams carrying a substituent

R 5 R 6

-O-C-SO 3 H

  (or a pharmaceutically acceptable salt thereof) at the 1-position and a 3-position acylamine substituent exhibit activity against a range of bacteria

gram-negative and gram-positive -

  Representative members of this novel family of 8-lactam antibiotics according to the present invention are those encompassed by the formula

-2 -4

R -NH-C-C-R 3 R

4 C N C-SO 3 H

  as well as their esters and salts.

  As they are used in Formula I and

  throughout the description, the symbols have the

definitions below.

  R is an acyl radical, a hydrogen atom or a group which is a precursor of the amine function; R 2 is a hydrogen atom or a methoxy radical; R 3 and R 4 are the same or different and are each a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or substituted phenyl radical, or a 4-, 5-, 6- or 7-membered heterocycle (hereinafter referred to as by R 7), or one of the substituents R 3 and R 4 is a hydrogen atom and the other is an azide, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl or carboxyl, or a radical of formula -CH 2 X 1, -SX 2,

X X

13 3 "

  -O-X 2, -O-C-X 4, -S-C-X 4, or -A-C-N X 6 X 7

X 5 X 5

  X 1 is azide, amine (-NH 2), hydroxy, alkanoylamine, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl) sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X 2 or -O-X 2; X 2 is an alkyl, substituted alkyl radical,

  phenyl, substituted phenyl, phenylalkyl, (substituted phenyl) -

  alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl) carbonyl or heteroarylcarbonyl; one of X 3 and X 4 is a hydrogen atom and the other is a hydrogen atom or an alkyl radical, or X 3 and X 4 taken together with the carbon atom to which they are attached form a cycloalkyl radical;

  X 5 is a formyl, alkanoyl, phenyl-

  carbonyl, (substituted phenyl) carbonyl, phenylalkylcarbonyl, (substituted phenyl) alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl

(NH 2-C-)

  (substituted amino) carbonyl, or cyano (-CEN); A is a radical of formula CH = CH-, -CH 2 -CH = CH-, (CH 2) N - (CH 2) n, -O-, - (CH 2) n, -NH-, or (CH 2) n, S-CH 2; is 0, 1, 2 or 3; n 'is 1 or 2; X 6 and X 7 are identical or different and are each a hydrogen atom or an alkyl radical, or

-2534253

  X 6 is a hydrogen atom and X 7 is an amine, substituted amine, acylamine or alkoxy radical; and R 5 and R 6 are the same or different and are each hydrogen, alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or R 7, or R 5 and R 6 taken together with carbon atom to which they are attached, form a cycloalkyl radical or R 7, or one of the substituents R 5 and R 6 is a hydrogen atom and the other is an azide radical, halomethyl,

  dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenyl-

  ethenyl, 2-phenylethynyl or carboxyl, or a radical of O n

  formula -CH 2 X 1, -S-X 2, -O-X 2, or -A-C-NX 6 X 7.

  The definitions of various terms used to describe the e-lactams according to the present invention are as follows. These definitions apply to terms as used throughout the

  description (unless limited in

  specific), either as such or as a

  parts of larger groups.

  The terms "alkyl" and "alkoxy" denote straight or branched chain radicals.

  radicals having 1 to 10 carbon atoms.

  The terms "cycloalkyl" and "cycloalkenyl" refer to cycloalkyl and cycloalkenyl radicals having

3, 4, 5, 6 or 7 carbon atoms.

  The term "substituted alkyl" denotes an alkyl radical substituted by one or more radicals azide, amine (-NH 2), halogen atoms or groups hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy,

  phenyloxy, (substituted phenyl) oxy, R 7 -oxy, mefcapto, afkyl-

  thio, phenylthio, (substituted phenyl) thio, alkylsulfinyl

or alkylsulfonyl.

  The terms "alkanoyl", "alkenyl" and "alkynyl" denote straight or branched chain radicals

  radicals having 2 to 10 carbon atoms are preferred.

  The terms "halogen" and "halo" refer to

  fluorine, chlorine, bromine or iodine atoms.

  The term "protected carboxyl" refers to a carboxyl group which has been esterified with a conventional acid protecting group. These radicals are well known in the art; see, for example, U.S. Patent No. 4,444,333 protected carboxyl groups.

  preferred are benzyl, benzhydryl, t-

butyl and para-nitrobenzyl.

  The term "substituted phenyl" refers to a phenyl radical substituted with 1, 2 or 3 halogen atoms or amine (-NH 2), hydroxyl, trifluoromethyl, alkyl (from 1 to 4 carbon atoms), alkoxy (from 1 to 4 atoms of

carbon) of the carboxyl.

  The expression "4-, 5-, 6- or 7-membered heterocycle" (symbol "R 7") means an aromatic or nonaromatic radical, substituted or unsubstituted, containing one or more nitrogen, oxygen or sulfur atoms. Examples of substituents are halogen atoms and

  oxo (= O), hydroxy, nitro, amine, cyano, trifluoro-

  methyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, 2-furylimine

_CH = N-

  benzylimine and substituted alkyl (of which the alkyl radical has 1 to 4 carbon atoms) A "4-, 5-, 6- or 7-membered heterocycle" type is the "heteroaryl" radical The term "heteroaryl" refers to 4-membered heterocycles, Examples of heteroaryl radicals are pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl and oxazolyl radicals. Examples of nonaromatic heterocycles (i.e., fully or partially saturated heterocyclic radicals) are azetinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, and the like.

  imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydro-

  substituted or unsubstituted pyrimidinyl, dihydrothiazolyl and hexahydroazepinyl Examples of heterocycles

  substituted with 4, 5, 6 or 7 members are the radicals 1-

  alkyl-3-azetinyl, 2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-

  2-oxo-1-imidazolidinyl, 3-benzylimino-2-oxo-1-imidazolidin

  yl, 3-alkyl-2-oxo-1-imidazolidinyl, 3-phenyl (or phenyl)

  substituted) -2-oxo-1-imidazolidinyl, 3-benzyl-2-oxo-1-

  imidazolidinyl, 3- (2-aminoethyl) -2-oxo-1-imidazolidinyl,

  3-amino-2-oxo-1-imidazolidinyl, 3-l (alkoxycarbonyl) aminol

  2-oxo-1-imidazolidinyl, 3- [2- (alkoxycarbonyl) aminol]

  Ethyl-2-oxo-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2-

  oxo-3-oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl, 2-

  oxo-1-hexahydroazepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-

  furanyl, 2,3-dioxo-1-piperazinyl, 2,5-dioxo-1-piperazinyl,

  4-alkyl-2,3-dioxo-1-piperazinyl and 4-phenyl-213-dioxo-1-

  piperazinyl. The term "substituted amine" refers to a radical of formula NY 1 Y 2 wherein Y 1 is a hydrogen atom or an alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl) alkyl radical, and Y 2 is a radical alkyl,

  phenyl, substituted phenyl, phenylalkyl, (substituted phenyl) -

  alkyl, hydroxy, cyano, alkoxy, phenylalkoxy or amine

(-NH 2).

  The term "substituted alkanoyl" encompasses in its

  scope of the compounds of formula (substituted alkyl) -

  O -C (wherein "substituted alkyl" has the same definition

  than above) and the phenylalkanoyl radical.

  The term "acyl" refers to all organic radicals derived from an organic acid (i.e.

  carboxylic acid) by removal of the hydroxyl group.

  Certain acyl radicals are of course preferred, but this should not be regarded as a limitation of the scope of the present invention. Examples of acyl radicals are the acyl radicals which have been used in the past to acylate antibiotics of the B-lactam series, including acid

  6-aminopenicillanic acid and its derivatives and 7-amino acid

  cephalosporanic and its derivatives; see, for example, Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972), German Patent Application Publication No. 2,716,677, Belgian Patent No. 867,994, German Patent No.

  United States of America N 4 152 432, the United States Patent

  United States No. 3,971,778, United States Patent No. 4,172,199, and British Patent No. 1,348,894. The parts of these references which describe various acyl radicals are incorporated herein by reference. The following list of acyl radicals is presented to give additional examples of the term "acyl";

  it should not be considered as limiting this term.

  Examples of acyl radicals are: (a) aliphatic radicals having the formula O if

R -C-

  wherein Ra is an alkyl radical; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen atoms or cyano, nitro, -amino, mercapto,

alkylthio or cyanomethylthio.

  (b) carbocyclic aromatic radicals having the formula Rc

R - O

CH 2) '- C-,

R -c CH-C- Re o

CH 2 -O-C-,

-o

) -CH 2 '

o he.

-CH 2-c-

  OR where N is 0, 1, 2 or 3; Rb, Rc and Rd are each, independently, a hydrogen or halogen atom or a hydroxyl, nitro, amine, cyano, trifluoromethyl, alkyl radical of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl; and R is an amine or hydroxyl radical, a carboxylic salt, a radical

  protected carboxyl, formyloxy, a sulfosal, a sulpho

  amine, an azide radical, a halogen atom, or a radical

  hydrazine, alkylhydrazine, phenylhydrazine or l (alkylthio)

  thioxométhyllthio. Preferred carbocyclic aromatic acyl radicals include those having the formula O.

/ 1 to Il.

c Hf C-c-

Rb

-34,253

E sI

CMH 2 NH 2

  ## STR5 ## where R.sub.1 is preferably a carboxylic salt or a sulfosal and wherein R.sub.1 is preferably

  a carboxylic salt or a sulfosal).

  (c) heteroaromatic radicals having the formula ## STR1 ## wherein Rf (CH 2) n-C-, Rf-CH C Re Rf -O-CH 2 -C-, O. Rf-S-CH 2 -C,

O O

3 O He He

OR Rf-C-C-

  wherein N is 0, 1, 2 or 3; Re has the same definition as above; and Rf is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring which contains 1, 2, 3 or 4 (preferably 1 or 2) nitrogen atoms,

  of oxygen or sulfur Examples of heterogeneous nuclei

  cyclic are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl radicals. Examples of substituents are halogen atoms and hydroxyl, nitro, amine, protected amine, cyano, trifluoromethyl, alkyl radicals. from 1 to 4 carbon atoms, alkoxy from 1 to 4 carbon atoms, O o

or HOOC H-CH 2 -O-C-NH-

NH

  The preferred heteroaromatic acyl radicals include the radicals corresponding to the preceding formulas

  in which Rf is a 2-amino-4-thiazolyl radical, 2-

  amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-

  1,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl or 6-amino-

pyridin-2-yl.

  (d) l (4-substituted-2,3-dioxo-1-piperine) radicals

  azinyl) carbonyllaminolarylacetyl having the formula

O O

  Embedded image in which R 8 is an aromatic radical (including aromatic carboxylic radicals such as those having the formula RR Rd and the heteroaromatic radicals encompassed by the definition of Rf); ## STR2 ## ; and Rh is an alkyl, substituted alkyl radical (in which the alkyl radical is substituted by one or more halogen atoms or cyano, nitro, amine or mercapto radicals), arylmethylene amine (ie of formula -N = Wherein Rg has the same definition as above), arylcarbonylamine (i.e., of the formula -NH-C-Rq wherein Rg has the same definition as above) or alkylcarbonylamine.

  The radicals E (4-substituted-2,3-dioxo-1-piper-

  azinyl) carbonyllaminolarylacetyl preferred include those

  in which Rh is an ethyl, phenyl-

  methylene-amine or 2-furylmethylene-amine.

  1 (e) (substituted oxyimino) arylacetyl radicals having the formula

-C-C = N-O-R

  Wherein Rg has the same definition as above and R1 is a hydrogen atom or a radical Rc, alkyl, cycloalkyl, alkylaminocarbonyl, arylaminocarbonyl (i.e., of formula -C-NH-Rg); wherein Rg has the same definition as above) or substituted alkyl (the alkyl radical is substituted by one or more halogen atoms or cyano, nitro, amine, mercapto, alkylthio, aromatic radicals (as defined by Rg), carboxyl (including their salts), amide, alkoxycarbonyl, phenylmethoxycarbonyl,

  diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, di-

  hydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl or dialkoxyphosphinyl. Preferred (substituted oxyimino) arylacetyl radicals include those in the formula of which Rg is a 2-amino-4-thiazolyl radical. The radicals in the formula of which R 1 is methyl are also preferred.

  ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2

  trifluoroethyl or 1-carboxycyclopropyl.

  (f) (Acylamino) arylacetyl radicals having the formula o

-C-CH-NH-C-R.

  in which R has the same definition as above and R 1 is a radical of formula R c

  -R - (CH 2) n-o-, an amine radical, alkylamine, (cyanoalkyl) -

  amine, amide, alkylamide, (cyanoalkyl) amide, or a radical of formula NH

-CH 2 -N C N

NH O

1 CH CH 2-C-NHCH 3,

C-CH-CH -C-NH-C 3 '

  HO ut 1 N 3 / O 2 -N (CH 2 -CH 2 -OH) 2, OH HN OOH

N,> LNN -CH,

HO

Yes c

HO I

  Preferred (acylamino) arylacetyl radicals having the above formula include those in the formula of which R 1 is an amine or amide radical. Also preferred are those radicals in which R 1 is phenyl or 2-thienyl

  (g) 11E 3-substituted-2-oxo-1-imidazoline radicals

  dinyllcarbonyllaminolarylacetyl having the formula where it

0 O C

S C-CH-NI-C-N N-Rk

J I I

R CH 2 -CH 2

  g in which R has the same definition as above and Rk

  is a hydrogen atom, an alkylsulfonyl radical, an aryl

  methylene amine (ie of the formula -N = CH-Rg in

  which R has the same definition as above), -

  Where R is a hydrogen atom or an alkyl or halogen substituted alkyl radical), an aromatic radical (according to the definition of R above), or an alkyl radical optionally substituted by one or more atoms

  of halogen or cyano radicals, nitro, amine or mercapto.

  The 3-substituted-2-oxo-1-imidazolidinyl radicals

  Preferred carbonylaminaminarylacetyl compounds among those of the above formula include those in the formula of which R is a phenyl or 2thienyl radical. The radicals in the formula of which Rk is a hydrogen atom or a methylsulfonyl, phenylmethylen-e radical are also preferred.

amine or 2-furylmethylene amine.

  The terms "salt" and "salts" refer to basic salts that are 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

  dicyclohexylamine salt, benzathine salts, N-

  methyl-D-glucamine and hydrabamine, and salts formed with amino acids such as arginine, lysine and similar amino acids Non-toxic and pharmaceutically acceptable salts are preferred, although other salts are also usable , for example for

isolate or purify the product.

  The salts are formed in a conventional manner by reacting the free acid form of the product with one or more equivalents of the appropriate base providing the desired cation in a solvent or in a medium in which the salt is insoluble, or in water and then removing the water by freeze-drying. Neutralizing the salt with an insoluble acid such as a cation exchange resin in the hydrogen form (eg a polystyrene sulfonic acid resin such as "Dowex 50"), or with the aid of an aqueous acid, and by extraction with an organic solvent, for example ethyl acetate, dichloromethane or a similar solvent, it is possible to obtain the

  free acid form and, if necessary, form another salt.

  E-lactams carrying a substituent

R 5 R 6

  -OC-SO 3 H (or a salt thereof) at the 1-position and an amine or acylamine substituent at the 3-position contain at least one chiral center the carbon atom (at the 3-position of the β-lactam nucleus) at which the amine or acyl substituent,

  The present invention relates to -

  lactams which have been described above, in which the

  stereochemistry at the chiral center at position 3 of the core of B-

  lactam is the same as the configuration on the carbon atom occupying position 6 of natural penicillins (penicillin G for example), and that the configuration on the carbon atom occupying position 7 of cephamycins

  natural products (cephamycin C, for example).

  With regard to the preferred β-lactams of formula I, the developed formulas have been designed to show the stereochemistry at the chiral center in

position 3.

  Also included in the scope of the present invention are mixtures

  racemates that contain the β-lactams described above.

  E-lactams carrying a substituent R 5 R

R 5 / R 6

  -OC-3 H (or a salt thereof) in position 1 of the nucleus of-lactam and an acylamine substituent at the 3-position of the β-lactam nucleus are active against a variety of gram-negative organisms and gram-positive The substituent

R R

  / 6 -O-C-SO 3 H (optionally in the form of salt) is essential

  to the activity of the compounds according to the present invention.

  The compounds of the present invention can be used as agents to combat bacterial infections (including urinary tract infections and respiratory infections) in certain mammals such as domestic animals (eg dogs, cats, cows). , horses, etc.) and

in humans.

  To combat bacterial infections in mammals, a compound according to the present invention can be administered to a diseased mammal at a rate of about 1.4 mg / kg / day to about 350 mg / kg / day, preferably about 14 mg / kg / day. mg / kg / day to approximately 100 mg / kgc / day All modes of administration that have been used in the past to reach the focus of penicillin and cephalosporin infection are also considered with the new B family. These modes of administration include the oral, intravenous, intramuscular and

form of suppository.

  The β-lactams according to the present invention can be prepared from an amino acid having the formula AOHR

NH 2 CH-C-R 3

  o C OH We begin by protecting the amine group with the aid of a

  conventional protective group (for example a radical t-

  butoxycarbonyl, benzyloxycarbonyl, o-nitrophenylsulfenyl,

2534-25 3 -

  etc.), which gives a compound of formula

-III OH

Oi \ R 4

A -NE-CH C R 3

11

O "CO I

  In formula III and throughout the description, the.

  symbol "A 1" means a nitrogen protecting group.

  The carboxyl group of the protected amino acid of formula III is then reacted with an amine having the formula

IV R

NH 3 -O -C-503

  The reaction is in the presence of a combination agent.

  such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide or dicyclohexylcarbodiimide, and gives a salt of the compound having the formula

V OH R

  The hydroxyl group of a compound of formula V (or a salt thereof) is converted to a grouping of a compound of formula (V) or a salt thereof. labile, using for example a conventional reagent such as methanesulfonyl chloride (the methanesulfonyl radical

is symbolized below by "Ms").

  The totally protected compound of formula O Ms R is cyclized

VI '1 %% "

Al-NH-C Hi C \ R 3

I '' R 5 N / R -

C-NH-O -C-SO 3 H '

  t 3 or a salt thereof, by treating it with a base, potassium carbonate by t. The reaction is preferably carried out in an organic solvent such as acetone under reflux conditions to give a compound having the formula VII R 4.

A -NH-CH-C-R 3

I 'It 5 /

C "N-O C SO 3 H,

O

or a salt of it.

  Alternatively, it is possible to cyclize a compound of formula V without first converting the hydroxyl group to a labile group. Treatment of a compound of formula V (or a salt thereof) with triphenylphosphine and the diethylazodicarboxylate or carbon tetrachloride and triethylamine gives a compound of formula VII The two methods described above for the cyclization of a compound of formula V result in a reversal of the stereochemistry at the level of the atom of

  carbon which is bonded to the substituents R 3 and R 4.

  The protection of the 3-amine substituent of a compound of formula VII can be omitted by using recognized techniques in this field. If, for example, the protecting group is the tbutoxycarbonyl radical, trifluoroacetic acid can be used to suppress protection of the amine group If the protective group is the benzyloxycarbonyl radical, it is possible to use a catalytic hydrogenation (using palladium on charcoal for example). If the protective group is the o-nitrophenylsulfenyl radical, it is possible to use para-toluenesulfonic acid in combination with parathiocresol The compound whose protection has been removed has the formula

VIII R

= 4 NH-CH-c-a N 2 -f | 3 R 5 / R 6

/ C-N-O C-SO 3 H

O *

2534253 -

  optionally in the form of a salt, and is a key intermediate for preparing the compounds according to the present invention The compounds of formula VIII form an integral part of the present invention. Well known acylation techniques can be used to convert a compound of formula VIII to a corresponding compound having formula IX

R 4

R 1-NH-CH C-R 3

3 hours

> C N O O C 53 H,

or in a salt of it.

  Examples of techniques include reaction with a carboxylic acid (R-OH) or a carboxylic acid halide or a corresponding carboxylic acid anhydride. Reactions with a carboxylic acid are best in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming

  in situ a reactive intermediate, such as N-hydroxy-

  benzotriazole or 4-dimethylaminopyridine In cases where the acyl radical (R 1) contains reactive functional groups (such as amine or carboxyl groups), it is optionally necessary to start by protecting these functional groups, and then to carry out the reaction. acylation reaction, and finally to delete ia

protection of the resulting product.

  The products of formula I wherein R 2 is a methoxy radical may be prepared from the corresponding compounds of formula VII wherein A 1 is a benzyloxycarbonyl radical. The halogenation (preferably chlorination) of the amide nitrogen of a compound of formula VII (A 1 is a benzyloxycarbonyl radical) gives a compound having the formula ## STR3 ##

-.CN - (- O -C-O 3,

or a salt of it.

  The reagents and procedures of N-

  Examples of reagents are 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 combination of two-phase solvents (water-methylene chloride, for example) in the presence of a base such as sodium borate decahydrate.

reduced temperature.

  Reaction of a compound of formula X with a methoxylating agent, for example with an alkali metal methoxide, gives a compound (in combination with its enantiomer if R 3 and R 4 are identical or if X is a racemic mixture) having for formula

CH 20-C-NH R 3

C N -O C, -03 H,

O 3

or a salt of it.

  The reaction can be carried out in an organic solvent, for example in a polar organic solvent

  such as tetrahydrofuran, at a reduced temperature.

  Or, we can transform a compound of

  formula V If, in which A 1 is a benzyloxy radical

  carbonyl, to a compound of formula XI using a single-step procedure. The methoxylating agent can first be mixed with a compound of formula VII (A is a benzyloxycarbonyl radical), and then the reaction reagent is added.

  N-chlorination in the reaction mixture.

  The conversion of the compounds of formula XI to the desired products of formula I can be carried out using the procedures described above for the conversion of an intermediate of formula VII into a

  produced according to the present invention.

  The starting materials of formula II can easily be obtained using procedures recognized in the art; see, for example, Synthesis, 5.p 216 (1979) and J Orq Chem, 44: 3967 (1979). 4 The following examples are forms of

  specific embodiments of the present invention.

EXAMPLE 1

  Dipotassic salt of 1 3 S-E 3 a (Z) acid, 48 l 1-2-llEl 1- (2-

  amino-4-thiazolyl) -2-11-methyl-2-oxo-1- (sulfomethoxy) -3-

  azetidinylllaminol-2-oxo-6-thyllene-aminoloxyl-2-methylpropanoic acid A) Aminoxymethanesulfonic acid Acetone was added

  oxime (1.46 g, 20 mmol) to a suspension of a 60% dispersion of sodium hydride in mineral oil (0.8 g, 20 mmol) in 16 ml of dry dimethylsulfoxide was then added fractions of sodium bromomethanesulfonate (3.94 g, 20 mmol) The reaction mixture was heated at 90-95 ° C for 4 hours under nitrogen, then cooled and washed twice with 250 ml. The product solidified, washed with 100 ml of dichloromethane, then filtered and dried over phosphoric anhydride to give 3 g of crude material. this in 20 ml of water and added tetrabutylammonium bisulfide (7.5 g, 22 mmol) The ion product was extracted

  paired thus obtained, twice with 200 ml of dichloro-

  methane The solution in dichloromethane was dried over sodium sulphate and then concentrated in vacuo. The hydrolysis of the acetone oxime was carried out by heating it in vacuo.

  ml of 2N hydrochloric acid at 130 ° C. for 4 hours.

  This solution was concentrated under vacuum in water (twice) and then in acetonitrile. The product solidified by addition of dichloromethane, and was filtered and dried under vacuum to give 2.5 g. of the titrel compound

  B) Potassium salt of O-sulfomethyl-ce-N-hydroxamate

  t-butoxycarbonyl-L-threonine aminoxymethanesulfonic acid was added

  (1.14 g, 8.9 mmol) to a solution of t-butoxycarbonyl-L-

  Threonine (1.96 g, 8.9 mmol) in 16 ml of water and 4 ml of OC tetrahydrofuran was adjusted to pH 4.5 with 1 N potassium hydroxide and added dropwise to 1 ml. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.87 g;

  9.7 mmol) in 8 ml of water.

  at room temperature for 2 hours, during which time the pH was maintained between 4 and 4.5 by adding 1N sulfuric acid from time to time. The product ions were paired with tetrabutylammonium bisulfate. (3.05 g, 8 mmol) at pH 2.8 and was extracted from

  aqueous solution with four 100-ml portions of dichloro-

  methane The solution in dichloromethane was dried over sodium sulfate and concentrated in vacuo to give

  p obtain 4.5 g of product in the form of its tetra-

  Butylammonium was converted to potassium salt by ion exchange on 150 ml of "Dowex X" resin (0.7 meq K / ml), and after lyophilization,

obtained 2.63 g of the title compound.

  C) Tetrabutylammonium salt of O-hydroxamate

  sulfomethyl-a-N-t-butoxycarbonyl-L- (O-methanesulfonyl

  I threonine) Has a partial solution of potassium salt

  O-sulfomethyl-c-N-t-butoxycarbonyl-L-hydroxamate

  Threonine (2.37 g, 6.5 mmol) in 50 ml of dry pyridine at 0-5 ° C under nitrogen was added dropwise 0.8 ml (excess) of methanesulfonyl chloride. at room temperature for 4 hours, then concentrated in vacuo. The residue was dissolved in 10 ml of water, and 2.0 g (6 mmol) of tetrabutylammonium bisulfate was added at pH 2.8. chloroform extracted the paired ionic substance. The chloroform layer was dried and concentrated in vacuo to

obtain 2.6 g of crude product.

  D) Potassium salt of C 3 S- (3 a, 4 e) 1-3 (1,1-dimethyl)

  ethoxy) carbonyllaminol-4-methyl-2-oxo-1- (sulfométhoxy) -

azetidine

  Acetone salt was dissolved in 5 ml of acetone.

  butylammonium of O-sulfomethyl-α-N-t-butoxy-hydroxamate

  Carbonyl-L- (O-methanesulfonylthreonine) (2.6 g, 4.0 mmol), and the solution was added dropwise to a refluxing suspension of 2.2 g of potassium carbonate in 65 ml of acetone. The reaction mixture was refluxed for 3 1/2 hours, then the reaction mixture was cooled, filtered and concentrated in vacuo. The residue was dissolved in 10 ml of 0.5M KH 2 PO 4 at pH 4.5. 5.5, and the pH was adjusted to 2.8. The product was extracted four times with 100 ml portions of dichloromethane, and the combined extracts dried and dried.

  concentrated them under vacuum to obtain 1.52 g of

  lactam, ion paired with tetrabutylammonium, crude.

  The potassium salt was ion exchanged through 50 ml of "Dowex 50 X" resin (0.7 meq K / ml) to obtain, after lyophilization, 0.53 g of crude material, which was again purified by chromatography through 100 ml of "HP-20" using water as eluent. The appropriate fractions were pooled.

  and lyophilized to give 0.245 g of product.

  Calc analysis for C 10 H 17 N 207 SK 1.2 H 20:

  C, 32.46; H, 5.28; N, 7.57; S, 8.66.

  Found: C, 32.52; H, 4.76; N, 7.43; S, 8.30.

  E) 13 S- (3 a, 4 e) 1-1-Sulfomethyl-3-amino-4-methyl-2-oxo-1

  azetidine Potassium salt was suspended from the

  1 3 S- (3ct, 4) 1-3-1E (1,1-dimethylethoxy) carbonylaminamin-4-

  methyl-2-oxo-1- (sulfomethoxy) azetidine (0.245 g, 0.68 g)

  mmol) in 0.5 ml of dichloromethane and 0.5 ml of anisole.

  The reaction mixture was cooled to 0 ° C and 1.0 ml of trifluoroacetic acid was added under nitrogen. The reaction mixture was stirred for one hour and then concentrated in vacuo to a residue which was made The residue is triturated with ether and the ether is decanted to give the product.

  desired in the form of a white solid.

  F) Potassium salt of the diphenylmethyl ester of

  1 3 S-1 3 a (Z), 48 ll-2-lll 1- (2-amino-4-thiazolyl) -2-

  11 4-Methyl-2-oxo-1- (sulfomethoxy) -3-azetidinylaminol

  2-oxo-ethylidenealaminoloxyl-2-methylpropionic acid (Z) -2-amino-a-11 2-

  (Diphenvlméthoxy) -1,1-dimethyl-2-oxo-ethoxyl-iminol-4-

  Thiazole acetic acid (0.30 g, 0.68 mmol) and hydroxybenzotriazole hydrate (0.10 g, 0.68 mmol) in dry dimethylformamide (4 ml) were added under nitrogen.

  10 to 0 C, then N, N'-dicyclohexyl was added in portions.

  carbodiimide (0.14 g, 0.68 mmol) After this addition,

  the reaction mixture was added at 0 ° C for one hour.

  j | It was then added-a solution of 3-amino-1-

  crude (sulfomethoxy) azetidine above (about 0.68 mmol)

  in 10 ml of dimethylformamide and 0.5 ml of N, N-diiso-

  The reaction mixture was stirred at 0 ° C for one hour and then at room temperature overnight. The solution was filtered and the filtrate concentrated in vacuo. The residue was dissolved in 50 ml of chloroform. Dichloromethane and was washed with 2 ml of water. After evaporation of the dichloromethane, 0.372 g of crude product was obtained. This was passed through 30 ml of Dowex 50® (0.degree. 7 meq K / ml) using water to obtain, after lyophilization, 0.211 g of crude product.

  t Contaminated with hydroxybenzotriazole.

  | G G) Dipotassium salt of the acid 1 3 S-1 3 a (Z), 4 Bll-2-Ell 1- (2-

  amino-4-thiazolyl) -2H-4-methyl-2-oxo-1- (sulfomethoxy) -

  3-azétidinyllaminol-2-oxo-éthylidènelaminoloxyl-2-

  Methylpropanoic acid 0.211 g of ester potassium salt was dissolved

  1 3 S-1 3 a (Z), 45 II-2-EL-1- (2-amino) -diphenylmethyl

  4-thiazolyl) -2-11 4-methyl-2-oxo-1- (sulfomethoxy) -3-

  azétidinyllaminol-2-oxo-2-methyl-éthylidènelaminoloxyl

  propionic in 1.8 ml of dichloromethane, 0.5 ml of anisole

  35 and 1.5 ml of trifluoroacetic acid, and the solution was stirred

  The reaction mixture was then concentrated in vacuo and evaporated twice in benzene. The residue was washed with a 1: 1 mixture of ether. and ethyl acetate followed by a 1: 1 mixture of ether and acetonitrile to give a white solid. This solid was dissolved in 1.0 ml of 0.5M KH 2 PO 4 at pH 5. 5, the solution was adjusted to pH 6.5 with 1 N potassium hydroxide and chromatographed on ml HP-20 with water to obtain 53 mg of the compound.

  of title, melting point 200 C with decomposition.

  Calc Analysis for C 14 H 17 N 50952 K 2 2.75 H

  C, 28.44; H, 3.84; N, 11.85; S, 10.84.

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

EXAMPLE 2

  1 2 S-E 2 a, 3 B (Z) 11 H-11 3-ll (2-amino-4-thiazolyl) (methoxy)

  imino) acetyllaminol-2-methyl-4-oxo-1-azetidinyl oxylmethane

  Using the procedure of Example 1, but replacing the acidethiazole acetic acid used in part (F) of Example 1 by an equimolar amount of (2) -2-amino-al (methoxy) acid. ) -iminol-4-thiazole-acetic,

  the title compound is prepared in the form of the mono-

  potassic as a hygroscopic solid after dissolution in acetonitrile and removal of acetonitrile by vacuum distillation several times IR spectrum: SO 3 (1030 cm 1); lactam

(1778 cm) -

  Calc analysis for C 11 H 4 N 50752 K 0.1 CH 3 CN:

  C, 38.11; H, 4.82; N, 15.92; S, 12.56.

  Found: C, 37.94; H, 5.36; N, 15.92; S, 12.56.

EXAMPLE 3

  Acid 1 2 S-1 2 ", 3 e (R) ll-11 3-llEEE1 4-ethyl-2,3-dioxo-1-

  piperazinyl) carbonyllaminolphénylacétvllaminol-2-methyl-4-

  oxo-1-azetidinyloxy methanesulfonias By following the procedure of Example 1 but replacing the thiazole acetic acid used in the procedure.

  part (F) of Example 1 with α-11 (4-ethyl-2,3

  dioxo-1-piperazinyl) carbonylaminolphenylacetic, the title compound is obtained in the form of its monopotassic salt, which is a hygroscopic solid IR spectrum:

503 (1038 cm); -Lactam (1775 cm)

  Calc Analysis for C 20 H 24 N 509 SK 1.6 H 20

  C, 41.53; H, 4.74; N, 12.11 S, 5.54.

  Found C, 41.53; H, 4.46; N, 11.13; S, 5, I 61.

EXAMPLE 4

  (S) -3-Benzyloxycarbonylamino, -4-methyl-2-oxo (sulfomethoxy) -

  azetidine Following the procedure of Example 1, parts (A) to (D), but replacing in part (B) the

  t-butoxycarbonyl-L-threonine with benzyloxycarbonyl

  serine, the title compound is obtained in the form of its potassium salt IR spectrum SQ 3 (1025 cm) lactam (1775 cm)

  Following the procedures described.

  previously, the following compounds are prepared

  Mono-Potassium Salt of the acid (3 S-trans) -El (2-

  amino-4-thiazolyl) (methoxyimino) acetylaminol-4-methyl-2-

  oxo-1-azetidinyllloxymethanesulphonic acid.

  Monopotassic salt of (3S-trans) -LE <2- acid

  amino-4-thiazolyl) E (2,2,2-trifluoroethoxy) iminolacetylaminol

  4-methyl-2-oxo-1-azetidinyloxy-methanesulfonic acid.

  Monopotassium salt of the acid (3 S-trans-IEE (2-

  amino-4-thiazolyl) E (2-amino-2-oxoethoxy) iminolacetylaminol

  4-methyl-2-oxo-1-azetidinyloxy-methanesulfonic acid.

  Dipotassic salt of (3 S-trans) -1 (2-amino)

  4-thiazolyl) E (carboxymethoxy) iminolacetyllaminol-4-methyl-2-

  oxo-1-azetidinyloxy) methanesulfonic acid.

  Dipotassic salt of (3 S-trans) -1 (2-amino)

  4-thiazolyl) EE- (carboxycyclopropyl) oxyliminolacetylaminol-

  4-methyl-2-oxo-1-azetidinyl-oxylmethanesulfonic acid.

  Monopotassium salt of l 3 S-E 3 a <R), 4 e 1 l-lE 3-

  E (aminophenylacetyl) aminol-4-methyl-2-oxo-1-azetidinyl

oxylmnéthanesulfonique.

  Monopotassium salt of acid (3 S-tr years) -III 3-

  E (phenylacetyl) aminol-4-methyl-2-oxo-1-azetidinyloxyl

methane sulfonia.

  Monopotassic salt of (3 S-trans) -EE 3-1 (2-

  thienylacetyl) aminol-4-methyl-2-oxo-1-azetidinyl-yloxy

sulphonic methane.

  Mono-tassic salt of (3S-trans) -EE 3-E acid (2,6-

  S dimethoxyphenyl) acetylaminol-4-methyl-2-oxo-1-azetidinyl

oxyjimethanesulfonic -

  Monopotassium salt of E 3 S-E 3 a <R>, 4 Jl 1-

  EE 3-EEEE (aminocarbonyl) aminol-2-thienylacetyl-amino J-4-

  methyl-2-oxo-1-azetidinyl) -oxy-methanesulfonic acid.

  Dipotassic salt of 1 acid E 3 S-E 3 a (R), 4 e l) -E E 3-

  E (carboxyphenylacetyl) aminol-4-methyl-2-oxo-1-azetidinyl-1

oxylméthane-sulfonic acid.

  Dipotassium salt of E 3 S-E 3a acid

  E (phenylsulfoacetyl) aminol-4-methyl-2-oxo-1-azetidinyloxy-

methane.

  Potassium mono acid salt (3 S-trans) 1 EA 3-

  CE (2-Amino-4-thiazolyl) oxoacetylaminol-4-methyl-2-oxo-1-azetidinyloxyethylmethanesulfonic acid:

  Mono-Potassium Salt of the acid 3 S-E 3a (R), 4 ell-EE 3-

  E EEE 2-oxo 3-E (phenylmethylene) ami'nol-1-imidazolidinyl) -

  carbonyllaminolphenylacetyl) amino-4-methyl-2-oxo-1 -

  azékidinyl 1 oxylmethanesulfonic.

  Selomorphopotassic acid E 3 S-1 3 a (Z), 4 e II-1E 3-EE 2-

  furanyl (methoxyimino) acetyllamino-4-methyl-2-oxo-1

  azetidinyl loxylrnethanesulfonic acid.

  Monopotassic salt of 1 3 S acid (Z> I-EE 3 -EE (2-

  amino-4-thiazolyl) imethoxyimino) acetylaminol-2-oxo-1-

  azetidinyloxyoxymethanesulfonic acid.

  Dipotassium salt of E 3 S <Zfl-EE 3-EE acid (2-

  amino-4-thiazolyl) E (1-carboxy-1-methylethoxy) iminolacetyl 1-

  amino J-2-oxo-1-azetidinyl-yloxymethanesulfonic acid.

  Monopotassium salt of the acid E 3 S (Z) I-EE 3-EE (2-

  amin-4-thiazolyl) E (-2,2,2-trifluoroethoxy) iminolacetylaminol

  2-oxo-1-azetidinyl loxylmethanesulfonic acid

  Monopotassium salt of E 3 S (Z) 1 -EE 3 -EE acid (2-

  amino-4-thiazolyl> E (2-amino-o-2-oxo-ethoxy) iminolacetylamino 1-

  -2-oxo-1-azetidinylloxyethanesulfonic acid.

  Mono-Potassium Salt of 1 3 S-E 3 ct S), 4 1-EE 3-

  EEE <aminocarbonyl) aminol-2-thienylacetylaminol-2-oxo-1

  azetidinyl] oxy-3-x-ethanesulfonic acid.

  Dipotassic salt of 1 3 S-E 3-a (), 4 Bll-1-3-

  E (phenylsulfoacetyl) aminol-2-oxo-1-azetidinyloxy-methanesulfonic acid.

  Monopotassium salt of E 3 S-1 acid 3 "(R), 4 ll-EE 3-

  CEEEE (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyllaminolphenyl 1-

  acétyllaminol-2-oxo-1-azétidinylloxylméthanesulfonique.

  Monopotassium salt of E <3 S (Z) l-EE 3- acid

  El (phenoxyacetyl) aminol-2-oxo-1-azetidinyloxymethylmethane

  sulfonic acid. Monopotassium salt of (3S-cis) -EEE (2-amino)

  4-thiazolyl) (methoxyimino) acetylamino) -4-methyl-2-oxo-1

  azetidinyloxyethanesulfonic acid.

  Mono-Potassium salt of (3S-cis) -EE acid (2-amino-4-

  thiazolyl) E (2,2,2-trifluoroethoxy) iminolacetylaminol-4-

  methyl-2-oxo-1-azetidinyljoxylmethanesulfonic acid.

  Dipotassium salt of (3S-cis) -EE acid (2-amino-4-

  thiazolyl) E carboxymethoxy) iminolacetyllanminol-4-methyl-2-

  oxo-1-azetidinyl-oxy) methanesulfonic acid.

  Dipotassium salt of acid (3 S-cis) -EE 3-lE (2-

  amino-4-thiazolyl) 1 (1-carboxy-1-methylethoxy) iminolacetyl

  aminol-2-oxo-4-methyl-1-azetidinyl-yloxymethanesulfornic.

  Dipotassium salt of (3S-cis) -EE acid (2-amino-4-

  thiazo-lyl) E (1 -; carboxycyclopropyl) oxyliminolacetylamino) -4-

  Methyl-2-oxo-1-azetidinyl-1-oxy-methanesulfonic acid.

  Monopotassic salt of (3S-cis) -EEE (2-amino

  4-thiazolyl) I (2-amino-2-oxo-ethoxy) iminolacetylaminol-4-

  2-methyloxo-1-azetidinylmethylmethanesulfonic acid.

  Dipotassium salt of E 3 S-E 3 a <R) acid, 4 cll-EE 3-

  E (carboxyphenylacetyl) aminol-4-methyl-2-oxo-1-azetidinyl

Oxytethane sulfonic acid.

  Monopotassium salt of E 3 S-E 3 c (R) acid, 4 and 1 l-EE 3

  EEEE (4-ethyl-2,3-dioxo-1-piperazinyl) carbonyllaminol

  phenylacetylaminol-4-methyl-2-oxo-1-azetidinyloxymethane

sulfonic acid.

  Monopotassium salt of E 3 S-E 3 ct <S), 4 all-EE 3-

  Eure (aminocarbonyl) aminol-2-thienylacetylamino-4-methyl 1-2-

  oxo-1-azétidinyll-oxylméthanesulfonique.

  Monopotassium salt of l 3 S-1 3 a (R), 4 all-lE 3-

  E (aminophénylacétyl) amino-4-methyl-2-oxo-1-azétidinylloxyl-

methane

EXAMPLE 5

  (2 a, 3 a) -1-Sulfomethoxy-2- (aminocarbonyl) -3 - (((1,1-dimethyl)

  ethoxy) carbonyl) amino) -4-oxo-azetidine A) Erythro-3-hydroxy-D, Laspartic acid

  Erythro-3-hydroxy-D, L-acid was prepared.

  aspartic acid from trans-epoxysuccinic acid as

  described by C W Jones et al (Can J Chem 47,4363 (1969)).

  The trans-epoxysuccinic acid was prepared from

  fumaric acid as described by G. B Payne et al (J.

Org Chem 24, 54 (1959)).

  B) X-methyl erythro-3-hydroxy-D, L-aspartate To a suspension of 5.0 g (33.5 mmol) of erythro-3-hydroxy-D, L-aspartic acid in 50 ml of methanol The mixture was refluxed for 3 hours, then cooled to room temperature and evaporated in vacuo. 95% ethanol, and the pH was adjusted to 8.0 by addition of pyridine. The white solid was filtered and dried to give 5.2 g (95% yield) of the desired methyl ester. having a

  melting point of 210 C with decomposition.

  C) Erythro-3-hydroxy-D, L-asparagine The above ethyl-α-aspartate (4.0 g, 24.5 mmol) was dissolved in 40 ml of concentrated ammonia and the solution was shaken. overnight at room temperature The reaction mixture was evaporated in vacuo to a solid which was dissolved in very hot water. The pH was adjusted to 5.0 with hydrochloric acid. 6 N, and the solution was concentrated in vacuo to a volume of about 20 ml, then allowed to stand overnight at 5 ° C. The white crystalline mass was collected and dried to obtain 3.4 g (95% yield) of the desired product, having a melting point of 233 C with decomposition.

  D) Potassium salt of N-t-butoxycarbonyl-erythro-3-

  Hydroxy-D, L-asparagine Erythro-3-hydroxy-D, L-asparagine (7.0 g, 47 mmol) was suspended in 50 ml of water and then solubilized by addition. This solution was adjusted to pH 10.0 and maintained at this pH while adding thereto dropwise a solution of dicarbonate.

dedi-t-butyl (15.5 g, 71 mmol) in 20 ml t-butanol.

  The reaction mixture was stirred at room temperature overnight at room temperature. The t-butanol was removed in vacuo, and the aqueous residue was adjusted to pH 5.0 with acid. Hydrochloric acid 6N The solution was concentrated in vacuo to a small volume and then adjusted to pH 3.0 with 6 N hydrochloric acid. Removal of the solvent in vacuo gave a solid (20 g). ) containing the desired product in the form of the free acid and with a substantially quantitative yield, as well as inorganic salts. A portion (2.9 g) of this solid was taken up in water and dilute potassium hydroxide. at pH 6.5, then subjected to chromatography on 100 ml of "HP-20" resin

  using water, then a 1: 9 mixture of acetone and -

  of water, to obtain the desired potassium salt in the form

a residue (1.8 g).

  E) Tetrabutylammonium salt of aminoxymethane acid

  sulfonic acid Tetrabutylammonium bisulfate (1.02 g, 3 mmol) was added to a solution of 0.635 g (5-mmol) of aminoxymethanesulfonic acid in 2 ml of water, and the pH was adjusted to 10.0. The water was removed in vacuo, and the residue was triturated with methylene chloride. After filtration, the filtrate was dried over sodium sulfate and evaporated to give the residue. desired product as a residue (1.06 g, 2.88 mmol).

  F) Potassium salt of O-sulfomethyl-a-N-hydroxamate

  t-butoxycarbonyl-erythro-3-hydroxy-D, L-asparagine Nt-butoxycarbonyl-erythro-3-hydroxy-D, Lasparagine (0.792 g, 2.77 mmol) was dissolved in 3 ml of water. and the pH of the solution was adjusted to 2.4 (using dilute sulfuric acid). The solution was concentrated in vacuo to a residue which was concentrated in water (twice). ) and then in benzene (twice) This residue was dissolved in dry acetonitrile (4 ml) and dry tetrahydrofuran (8 ml) and the solution was cooled to OCA with this stirred solution, 0.424 g was added ( 2.77 mmol) of 1-hydroxybenzotriazole monohydrate followed by 0.572 g (2.77 mmol) of N, N'-dicyclohexylcarbodiimide The mixture was stirred at 0 ° C for 2 hours and then added dropwise.

  the tetrabutylammonium salt of aminoxymethane

  above sulfonic acid (1.06 g, 2.88 mmol) in 5 ml of acetonitrile After this addition, the reaction mixture was stirred at 0 ° C for 4 hours. The reaction mixture was then filtered and concentrated. Under vacuum to a residue 10 ml of water were added, and the residue triturated at 0 ° C. until solidified. The solid was filtered off, and the aqueous filtrate was concentrated to 3 ml. The pH was adjusted to 4.0, and fractionation was performed on 80 ml of Dowex (K) ion exchange resin. The appropriate fractions were collected and concentrated to a small volume. The pH was adjusted to 3.4, and the solution was subjected to "HP-20" resin chromatography to obtain, after lyophilization, 502 mg (46%) of the desired product, as a solid having

  a melting point of 145 QC with decomposition.

  Calc analysis for C 10 H 18 N 309 SK 0.71 H 2:

  C, 29.42; H, 4.80; N, 10.29; S, 7.85.

  Found: C, 29.42; H, 4.73; N, 10.04; S, 7.45.

  F) Tetrabutylammonium salt of O-sulfonated hydroxamate

  methyl-a-N-t-butoxycarbonyl-erythro-3-hydroxy-D, L-

  asparagine To a solution of the potassium salt of the above asparagine hydroxamate (104, 0.263 mmol) in 1 ml

  of water, 2.63 ml of tetrabutyl bisulfate was added.

  0.1M ammonium in 0.5M KH 2 PO 4 buffer at pH 5.5 The solution was concentrated to dryness, and the residue was triturated.

  with methylene chloride Filtration and -

  Evaporation of the methylene chloride layer gave the desired product as a residue (156 mg, 0.26 mmol).

  G) Potassium salt of (2a, 3a) -1-sulfomethoxy-2- (amino)

  carbonyl) -3 ((1,1-dimethylethoxy) carbonyl-amino) -4-oxo

  Azetidine The tetrabutylammonium salt of Osulfomethyl hydroxamate above (140 mg, 0.234 mmol) was dissolved in 1.6 ml of dry methylene chloride, and the solution was stirred with 1 g of dried 3 A molecular sieve, overnight The solution was taken with a syringe and diluted with 0.8 ml of dry methylene chloride. To this solution stirred at 50 ° C. under argon, 0.12 ml was added ( 0.85 mmol) of triethylamine, then, dropwise, 0.08 ml (0.42 mmol) of trifluoromethanesulfonic anhydride. The reaction mixture was allowed to warm to 30 ° C. for one hour and then 0 was added. After 5 minutes, the reaction mixture was concentrated in vacuo and then the residue was dissolved in 2 ml of acetone. The solution was cooled to 0 ° C. and a solution of 79 mg of toluene was added. potassium perfluorobutanesulfonate in 1 ml of acetone. Ether was then added, and the resulting Centrifugally treated by stirring with 2 ml of "Dowex 50 (K)" resin; in water, filtration and removal of water under vacuum, gave the crude desired potassium salt containing no amines. Chromatography of this crude potassium salt on "HP-20" resin using the water gave, after freeze-drying, 15 mg (20% yield) of the desired potassium salt, having a melting point of 1491 C with lactam) and 1696 cm-1 (broad, carbonyl amide and carbamate) . -31

Claims (10)

1 Compound of formula _ 2 R -Ni S C-R 3 I I '3 R 6 C N-O-O-C-SO 3 H,   optionally in salt or ester form, in which formula: R 1 is an acyl radical, a hydrogen atom or a group protecting the amine function; R 2 is a hydrogen atom or a methoxy radical; R 3 and R 4 are the same or different and are each a hydrogen atom or an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or substituted phenyl radical, or a 4-, 5-, 6- or 7-membered heterocycle, or the one of R 3 and R 4 is a hydrogen atom and the other is a radical   azide, halomethyl, dihalomethyl, trihalomethyl, alkoxy-   carbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -X 3 or a radical of formula -CH 2 -X 1, -S-X 2, -O-X 2, -O-C-X 4, X O 'x 5 13 'I   -S-C-X 4, or -A-C-NX 6 X 7; X 5 X 1 is an azide, amine (-NH 2), hydroxy, alkanoylamine, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl) sulfonyloxy, phenyl, substituted phenyl, cyano, -S-X 2 or -O-X 2; X 2 is alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl) alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl) carbonyl or heteroarylcarbonyl; one of X 3 and X 4 is a hydrogen atom and the other is a hydrogen atom or an alkyl radical, or X 3 and X 4 taken together with the carbon atom to which they are attached form a cycloalkyl radical; 32-2534253   X 5 is a formyl, alkanoyl, phenyl-   carbonyl, (substituted phenyl) carbonyl, phenylalkylcarbonyl, (substituted phenyl) alkylcarbonyl, carboxyl, alkoxycarbonyl, O O   aminocarbonyl (NH 2 -C), (substituted amino) carbonyl, or cyano (-CEN); A is a radical of formula -CH = CH-, -CH 2 -CH = CH-, - (CH 2) -n, - (CH 2) n, O, (CH 2) n, -NH-, or - (CH 2), - S-CH 2; is 0, 1, 2 or 3; n 'is 1 or 2; X 6 and X 7 are the same or different and are each a hydrogen atom or an alkyl radical, or X 6 is a hydrogen atom and X 7 is an amine, substituted amine, acylamine or alkoxy radical; and R 5 and R 6 are the same or different and are each a hydrogen atom or an alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or R 7 radical, or R 5 and R 6 together with the atom form of carbon to which they are attached, a cycloalkyl radical or R 7, or one of R 5 and R 6 is a hydrogen atom and the other is a radical   azide, halomethyl, dihalomethyl, trihalomethyl, alkoxy-   carbonyl, 2-phenylethenyl, 2-phenylethynyl or carboxyl, or a radical of formula -CH 2 X 1, -S-X 2, -O-X 2, or O -A-C-NX 6 X 7.   Compound according to claim 1, in which   wherein R 2 is a hydrogen atom.   Compound according to claim 2 wherein one of R 3 and R 4 is other than a hydrogen atom. Compound according to Claim 2, in the formula of which R 3 is a hydrogen atom and R 4 is a methyl radical.   The compound of claim 2 wherein R 3 is a methyl radical and R 4 is a hydrogen atom. Compound according to claim 2, in which   wherein R 5 and R 6 are each a hydrogen atom.   Compound according to claim 2, in which   wherein R 5 and R 6 are each methyl.   A compound according to claim 2, wherein R 1 is a (Z) -2-amino-al (1-carboxy-1-methylethoxy) imino) -4-thiazoleacetyl radical. 9 A compound according to claim 1, wherein wherein R 2, R 5 and R 6 are each a hydrogen atom, one of R 3 and R 4 is an alkyl radical, and the other is a hydrogen atom.   A compound according to claim 3 wherein R 2, R 3, R 5 and R 6 are each an atom   of hydrogen and R 4 is a methyl radical.   Compound according to claim 3, wherein R 2, R 4, R 5 and R 6 are each an atom   of hydrogen and R 3 is a methyl radical.   Compound according to claim 1, in which   formula of which R 1 is a hydrogen atom.   Compound according to claim 1, wherein R 1 is a protecting group for the amine function. Compound according to claim 1, which is   1 3 S-13A (Z), 4H-2-EL-1- (2-amino-4-thiazolyl) -2-11   methyl-2-oxo-1 - (- sulfométhoxy) -3-oxo-2-azétidinylllaminol   éthylidènelaminoloxyl-2-methylpropanoic.   Compound according to claim 1, which is   1 3 S- (3 a, 4)) 1-1-sulfomethoxy-3-amino-4-methyl-2-oxb-1   azetidine. A composition with a therapeutic action, in particular with an antibiotic action, characterized in that its active ingredient is a compound according to any one of Claims 1 to 15.