CH658858A5 - AZETIDINYL SULFONIC ACID AND THE LIKE. - Google Patents

Description

This invention relates to a new family of lactam antibiotics. It has been discovered that the β-lactam ring can be activated biologically by a substituent having the formula

R5 R6

\ /

-o-c-so3h

(or its salt) attached to the nitrogen atom in the nucleus.

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Ss-lactams having a substituent

Rs Râ

\ /

-0-C-S03H

(or its pharmaceutically acceptable salt) in position 1 and an acylamino substituent in position 3 have activity against a range of bacteria which do not take gram and which take gram.

Elements representing the new family of β-lactam antibiotics of this invention are included in the following formula:

I I * 5x ^ 6 ^ N— O— C — S03H,

or an ester or a salt thereof.

The symbols, as used in formula I and throughout the present description, are defined below.

Ri is an acyl;

R2 represents hydrogen or methoxy;

R3 and R4 are the same or different and each represents hydrogen, an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a heterocycle with 4, 5, 6 or 7 members (hereinafter called R7) or one of R3 and R4 represents hydrogen and the other represents an azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, - CE ^ Xj, - S — X2,

X3 X3 O

I I II

-0-X „-0-C-X4, -S-C-X4, or -A-C-NXÄ;

I. I

X5 X5

Xj represents an azido, amino (—NH2), hydroxy, alkanoyl-amino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl) sulfonyloxy, phenyl, substituted phenyl, cyano, - S — X2 or - O — X2;

X2 represents an alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl) alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl) carbonyl or heteroarylcarbonyl);

one of X3 and X4 represents hydrogen and the other represents hydrogen or an alkyl, or X3 and X4, when together with the carbon atom to which they are attached, form a cycloalkyl group;

Xs represents a formyl, alkanoyl, phenylcarbonyl, (substituted phenyl) carbonyl, phenylalkylcarbonyl, (substituted phenyl) alkylcar-bonyl, carboxyl, alkoxycarbonyl, aminocarbonyl

O

II

(NH2 — C—),

(substituted amino) carbonyl, or cyano (—C = N);

A represents - CH = CH—, CH2 - CH = CH—, (CH2) —n— (CH2) n— O—, - (CH2) n — NH—, or - (CH2) n— S - CH2;

n is 0, 1, 2 or 3;

n 'is equal to 1 or 2;

X6 and X7 are the same or different and each represents hydrogen or an alkyl, or X6 represents hydrogen and X7 represents an amino, substituted amino, acylamino or alkoxy; and

R5 and Rfl are identical or different and each represents hydrogen, an alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl or R7 or R5 and R6 together with the carbon atom to which they are attached are a cycloalkyl or R7, or one of R5 and

R6 represents hydrogen and the other represents an azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, - CH2X1;

O

II

-S-X2, -0-X2, or - A —C —NX „X ~.

Definitions of the various terms used to describe the β-lactams of this invention are given below. These definitions apply to terms as used in this specification (unless they are otherwise limited in specific cases) either individually or as part of a larger group.

The terms "alkyl" and "alkoxy" relate to straight chain groups and branched chain groups. Groups having 1 to 10 carbon atoms are preferred.

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

The term "substituted alkyl" relates to alkyl groups substituted with one or more of the azido, amino (- NH2), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyl-oxy, alkoxy, phenyloxy, (substituted phenyl) oxy groups. , R7-oxy, mercapto, alkylthio, phenylthio, (substituted phenyl) thio, alkylsulfinyl, or alkyl-sulfonyl.

The terms "alkanoyl", "alkenyl", and "alkynyl" refer to both straight chain and branched chain groups. Groups having 2 to 10 carbon atoms are preferred.

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

The term "protected carboxyl" relates to a carboxyl group which has been esterified with a conventional acid protecting group. These groups are well known in the art; see, for example, U.S. Patent Application 4,144,333, published March 12, 1979. Preferred protected carboxyl groups are benzyl esters. benzyhydryl, t-butyl, and / i-nitrobenzyl.

The term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino groups (—NH2), halogen, hydroxyl, trifluoromethyl, alkyl (from 1 to 4 carbon atoms), alkoxy (from 1 to 4 atoms carbon), or carboxyl.

The expression “a heterocycle with 4, 5, 6 or 7 members” (defined by “R7”) relates to substituted and unsubstituted, aromatic and non-aromatic groups containing one or more nitrogen, oxygen or sulfur atoms . Examples of substituents are the oxo (= 0), halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl groups of 1 to 4 carbon atoms, alkoxy groups of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, substituted phenyl, 2-furylimino

/ Ov, CH = N-

(lj).

benzylimino and substituted alkyl (where the alkyl group has 1 to 4 carbon atoms). One type of "heterocycle with 4, 5, 6 or 7 members" is the group "heteroaryl". The term "heteroaryl" relates to heterocycles with 4, 5, 6 or 7 members which are aromatic. Examples of heteroaryl groups are, substituted and unsubstituted, pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxa-zolyl, triazinyl, and tetrazolyl. Examples of non-aromatic heterocycles (i.e. fully or partially saturated heterocyclic groups) are the substituted and unsubstituted groups azetinyl, oxethanyl, thiethanyl, piperidinyl, piperazinyl, imidazolidi-nyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothia-zolyl and hexahydroazepinyl. Examples of heterocycles with 4, 5, 6 or 7 substituted members are 1-alkyl-3-azetinyl, 2-oxo-1-imidazolidi-nyl, 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.

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3- (2-aminoethyl) -2-oxo-1 -imidazolidinyl, 3-amino-2-oxo-1 -imidazolidinyl, 3 - [(alkoxycarbonyl) amino] -2-oxo-1 -imidazolidinyl, 3- [2- [(al-coxycarbonyl) -amino] ethyl] -2-oxo-l-imidazolidinyl, 2-oxo-l-pyrroli-dinyl, 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-2,3-dioxo-1-piperazinyl.

The term "substituted amino" refers to a group having the formula - NY ,, Y2 in which Yt represents hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl) al-kyl, and Y2 represents alkyl , phenyl, substituted phenyl, phenylalkyl, (substituted phenyl) alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino (—NH2).

The term "substituted alkanoyl" includes within its scope compounds having the formula (substituted alkyl)

O I!

-VS-

(in which "substituted alkyl" has been defined above) and phenylal-canoyl.

The term "acyl" refers to all organic radicals derived from an organic acid (i.e., a carboxylic acid) by extraction from the hydroxyl group. Certain acyl groups are, of course, preferred, but this preference should not be considered as limiting the scope of this invention. Examples of an acyl group are the acyl groups which have been used in the past to acylate β-lactam antibiotics, including 6-aminophenicillinic acid and its derivatives and 7-amincephalosporanic acid and its derivatives; see, for example, Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972), German Offenlegungsschrift 2,716,677, published October 10, 1978, Belgian patent 867.994, published December 11, 1978, US patent 4,152,432, published on May 1, 1979, US Patent 3,971,778, issued July 27, 1976, US Patent 4,172,199 issued October 23, 1979 and UK Patent 1,348,894 issued March 27, 1974. Parts of these references describe the groups acyl are incorporated into this application by reference. The following list of acyl groups is presented to better illustrate with examples the term "acyl"; this list should not be considered as limiting this term. Examples of acyl groups are:

(a) Aliphatic groups having the formula

O

II

Ra — C—

wherein Ra represents an alkyl; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, al-kylthio, or cyanomethylthio groups.

(b) Aromatic carbocyclic groups having the formula

"& rl ■

R.

"b

SHOCK-

RbÄ! Do-c „2X.

r.

"b

S-CH.

R

wherein n is 0.1, 2 or 3; Rb, Rc and Rd each independently represent hydrogen, halogen, hydroxyl, nitro,

amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl; and Re represents an amino, hydroxyl, a carboxyl salt, a protected carboxyl, formyl-oxy, a sulfo salt, a sulfoamino salt, an azido, halogen, hydrazino, alkylhydrazino, phenylhydrazino, or [(alkylthio) thioxomethyl] thio.

Preferred aromatic acyl carbocyclic groups include those having the formula

HO

CH

-VS-

HO '

H-C-

(Re is preferably a carboxyl salt or a sulfo salt) and

CH — i

(Re is preferably a carboxyl salt or a sulfo salt). (c) Heteroaromatic groups having the formula

O

II

rf— (ch2) „- c—,

O

II

rf-ch-c-,

I

R "

O

II

rf — o —ch2 — c—

O

II

rf — s — ch2 — c—,

O O

ii ii rf-c-c-,

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in which n is 0, 1, 2 or 3; Re has the same definition as above; Rr is a substituted, unsubstituted heterocyclic ring with 5, 6 or 7 members containing 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and sulfur atoms. Examples of heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, py-razinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Examples of substituents are: halogen, hydroxyl, nitro, amino, protected amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or

O

II

hooc — ch — ch, -0 —c — nh -

I

nh2

Preferred heteroaromatic acyl groups include groups having the above formulas wherein Rf represents 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidine-2-yl, 5-amino- 1,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl, or 6-ami-nopyridine-2-yl.

(d) The [[(4-substituted-2,3-dioxo-1-piperazinyl) carbo-nyl] amino] arylacety groups having the formula:

0 î / ^

-d-CH-NH-C-N N-R,

ì

g oo in which RE is an aromatic group (comprising carbocyclic aromatics such as those of the formula and heteroaromatics such as those included in the definition of rf); and rh is alkyl, substituted alkyl (where the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups), arylmethylene-amino (i.e. - n = ch —rg where rg has the same definition as above), arylcarbonylamino (i.e.

O

II

-nh-c-re in which rgÎTîa same definition as above) or alkylcarbo-nylamino.

Preferred [[(4-substituted-2,3-dioxo-1-piperazinyl) carbonyl] ami-no] arylacetyl groups include those in which rh represents ethyl, phenylmethylene-amino or 2-furylmethylene-amino. (e) Arylacetyl (substituted oxyimino) groups having the formula

O

II

—C — c = n — o —r |

I

Re in which rg has the same definition as above and ri represents hydrogen, rc, alkyl, cycloalkyl, alkylaminocarbonyl, arylamino-carbonyl (i.e.

O

- C — HN —Rg where rg has the same definition as above) or substituted alkyl (where the alkyl group is substituted with one or more substituents halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group (as defined by Rg), carboxyl (including its salts), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hy-droxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmé-thoxy) phosphinyl, or dialcoxyphosphinyl).

Preferred (substituted oxyimino) arylacetyl groups include those in which Rg is 2-amino-4-thiazolyl. The groups in which R 1 represents methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifiuoroethyl or 1-carboxycyclopropyl are also preferred.

(0 (acyiamino) arylacetyl groups having the formula

O O

He II

-C-CH-NH-C-R,

I

in which Rg has the same definition as above and Rj represents amino, alkylamino, (cyanoalkyl) amino, amido, alkylamido, (cya-noalkyl) amido,

iï \ r ^ f2 î

-CH2-NH-C —- CH-CH2-C-NK-CH3,

SO_-N (CH_-CH_-OH)

HO.

OH

OH

CH

OH

HO

VS-.

HO

Preferred (acylamino) arylacetyl groups of the above formula include groups in which Rj represents an amino or an amido. Groups in which Rg represents phenyl or 2-thienyl are also preferred.

(g) The [[[3-substituted-2-oxo-1-imidazolidinyl] carbonyl] -amino] arylacetyl groups having the formula:

O II

o oc

He H ^

-C-CH-NH-C-N N-R, I 1 I K

R CH2 CH2

g in which Rg has the same definition as above and Rk represents a hydrogen, an alkylsulfonyl, arylmethylene-amino (that is to say - N = CH - Rg in which Rg has the same definition as above) ,

O

- C —Rm

(where Rm represents hydrogen, alkyl or halogen-substituted alkyl), an aromatic group (as defined by Rg above), alkyl or substituted alkyl (where the alkyl group is substituted with one or more groups hydrogen, cyano, nitro, amino or mercapto).

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Preferred [[[3-substituted-2-oxo-1-imidazolidinyl] carbonyl] ami-no] arylacetyl groups having the above formula include groups wherein Rg is phenyl or 2-thienyl. The groups also preferred are those in which Rk represents hydrogen, methylsulfonyl, phenylmethylene-amino or 2-furylmethylene-amino.

The terms "salt" and "salts" relate to basic salts formed with inorganic and organic bases. Such salts include ammonium salts, alkali metal salts such as sodium and potassium salts (which are preferred), alkali-no-earth metal salts such as calcium and magnesium salts, salts with organic bases, for example the dicyclohexylamine salt, the benzathine, N-methyl-D-glucamine, hydrabamine salts, the salts with amino acids such as arginine, lysine and others. Pharmaceutically acceptable non-toxic salts are preferred, although other salts are also useful, for example in isolating or purifying 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, producing the desired cation in a solvent or medium in which the salt is insoluble, or in water and in extracting 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 resin of sulfonic acid such as Dowex 50) or with an aqueous acid and extraction with an organic solvent, for example l ethyl acetate, dichlorometane or the like, the free acid form can be obtained and, if desired, another salt can be formed.

Ss-lactams having a substituent

Rs RO

\ /

—O — C — SO, H

The compounds of this invention can be used as agents to combat bacterial infections (including urinary tract infections and respiratory tract infections) in mammals such as pets (e.g. dogs, cats, cows, horses and others) and in humans.

To combat bacterial infections in mammals, a compound of this invention can be administered to a mammal in need thereof, at a dose of from about 1.4 mg / kg / day to about 350 mg / kg / day, from preferably from about 14 mg / kg / day to about 100 mg / kg / day. All of the modes of administration which have been used in the past to administer penicillins and cephalosporias at the site of infection are also retained for use with the new family of β-lactams of this invention. Such methods of administration include oral, intravenous, intramuscular and suppository methods.

The ß-lactams of this invention can be prepared from an amino acid having the formula:

nh2-ch-

0H R

IV \\ R4 -C — R *

(ii)

-OH

The amino group is first protected with a conventional protective group (for example, i'-butoxycarbonyl, benzyloxycarbo-nyl, o-nitrophenylsulfenyl, etc.), producing a compound having the formula:

30

a1-nh-ch-

0h r

I \\ N 4 -c — r3

-Oh

(III)

(or its salt) in position 1 an amino or acylamino substituent in position 3 contains at least one center of rotatory power, namely the carbon atom (in position 3 of the ß-lactam nucleus) to which the substituent amino or acylamino is attached. The invention relates to the ß-lactams which have been described above in which the stereochemistry at the center of rotatory power in position 3 of the ß-lactam nucleus is the same as the configuration at the atomic level. of carbon in position 6 of naturally occurring penicillins (eg, penicillin G) and that configuration at the carbon atom in position 7 of cephamycins occurring (eg, cephamy-cine C).

With regard to the preferred β-lactams of formula I, the structural formulas have been drawn to illustrate the stereochemistry at the center of rotary power in position 3.

Also included within the scope of this invention are racemic mixtures which contain the β-lactams described above.

Ss-lactams having a substituent

\ /

—O — C — SO, H

In formula III, and throughout this patent description, the symbol "Aj" relates to a nitrogen protection group.

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

NH®-0 — C — lo ©

(IV)

The reaction continues in the presence of a coupling agent such as 45 l-ethyl-3- (3-dimethylaminopropyl) -carbodiimide or dicyclohexyl-carbodiimide, and gives a salt of compound having the formula:

a1-nh-ch-

-X "

OH R,

-C — r3

R5V sR6 -NH-O — C — S03H

(v)

The hydroxyl group of a compound of formula V (or a salt thereof) is converted to an leaving group using, for example, 55 a conventional reagent such as methanesulfonyl chloride (methanesulfonyl is hereinafter referred to as " Ms ").

The fully protected compound having the formula:

(or its salt) in position 1 of the ß-lactam nucleus and an acylamino substituent in position 3 of the ß-lactam nucleus have activity against a series of organisms which take up gram and which do not take up gram. The substitute

\ / 6

-O-C-SO3H

(or its salt) is essential for the activity of the compounds of this invention.

A1-NH-CH-

OMs R.

I 4 -C — R3

-NH-O — C — S03H

(VI)

65 or a salt thereof is cyclized by treatment with a base, for example potassium carbonate. The reaction is preferably carried out in an organic solvent such as acetone, under reflux conditions, and gives a compound having the formula:

7

658,858

a1-nh-ch-

= 4

-c-r,

I zR6

-n-0 — c — s03h

(vii)

or a salt thereof.

As a variant, the cyclization of a compound of formula V can be carried out without first converting the hydroxyl group into an leaving group. Treatment of a compound of formula V (or a salt thereof) with triphenylphosphine and diethylazodicarboxylate or carbon tetrachloride and triethylamine gives a compound of formula VII.

The two methods described above for closing the ring of a compound of formula V give as a result the reversal of the stereochemistry at the level of the carbon atom bonded to the substituents R3 and R4.

The deprotection of the 3-amino substituent of a compound of formula VII can be accomplished using techniques known in the art. If, for example, the protecting group is ï-butoxycarbonyl, trifluoroacetic acid can be used to deprotect the amino group. If the protecting group is benzyloxycarbonyl, catalytic hydrogenation (for example, palladium on carbon) can be used. If the protecting group is o-nitrophenylsulfenyl, /) - toluenesulfonic acid can be used in combination with p-thio-cresol. The deprotected compound has the formula:

nh2-ch-

§4

-c-r.

-not-

-o-c-so3h or a salt thereof, and is a key intermediate for preparing the compounds of this invention. The compounds of formula VIII form an integral part of this invention.

Well-known acylation techniques can be used to convert a compound of formula VIII to the corresponding compound having the formula:

r1-nh-ch-

§4

-c-r.

R

-not-

5 "v

—C — so3H

O Cl Il I

ch - 0-c-n-ch-

2 I

Ì4

-c-r,

I R5v m

-n — o — c "

so3h

Reactants and methods of N-chlorination of amides are known in the art. Examples of reaction agents are tert.-butyl hypochloride, 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 water / methylene chloride) in the presence of a base such as sodium decahydrate sodium borate. The reaction preferably takes place at a reduced temperature.

The reaction of a compound of formula X with a methoxylating agent, for example an alkali metal methoxide, produces a compound (in combination with its enantiomer if R3 and R4 are identical or if X is a racemic mixture) having the formula:

(VIII)

(IX)

or a salt thereof.

Examples of techniques include reaction with a carboxylic acid (Rt-OH) or a carboxylic acid halide or a corresponding carboxylic acid anhydride. Reactions with a carboxylic acid are facilitated in the presence of a car-bodiimide such as dicyclohexylcarbodiimide and a substance capable of forming a reactive intermediate in situ such as N-hydroxy-benzotriazole or 4-dimethylaminopyridine. In the case where the acyl group (RJ contains a reactive functionality (such as amino or carboxyl groups), it may be necessary to protect these functional groups first, then to carry out the acylation reaction, and finally to deprotect the resulting product.

The products of formula I in which R2 represents a methoxy can be prepared from the corresponding compound of formula VII in which At represents benzyloxycarbonyl. The halogenation (preferably chlorination) of the amide nitrogen of a compound of formula VII (Ax represents benzyloxycarbonyl) produces a compound having the formula:

O II

ch -o-c-nh-c

I

S

2CH3 §4 c-r

I 3R5w * 6

N — O — C — S03H

(xi)

30

(x)

or a salt thereof.

or a salt thereof.

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 A represents a benzyloxycarbonyl, can be converted into a compound of formula XI using a one-step process. The methoxylating agent can first be mixed with a compound of formula VII (Aj represents a benzyloxycarbonyl) and the N-chlorination reagent is then added to the reaction mixture.

The conversion of a compound of formula XI into the desired product of formula I can be carried out using the methods described above for the conversion of an intermediate of formula VII into a product of this invention.

The starting materials of formula II can be readily obtained using methods known in the art; see for example Synthesis, p. 216 (1979) and J. Org. Chem., 44 \ 3967 (1979).

The following examples are specific embodiments of this invention.

40 Example 1

[3S- [3a (Z), 4ß]] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [[4-methyl-2-oxo-1] acid dipotassium salt - (sulfomethoxy) -3-a: etidinvl] -amino J-2-oxoethylidene] amino Joxy J-2-methylpropanoic

A) Aminoxymethanesulfonic acid

45

Acetone oxime (1.46 g, 20 mmol) was added to a suspension of a dispersion of a mineral oil with 60% sodium hydride (0.8 g, 20 mmol) in 16 ml of dry dimethyl sulfoxide. Then 50 sodium bromomethane sulfonate (3.94 g, 20 mmol) was added in portions. The reaction was heated to 90-95 C for 4 hours under nitrogen, then cooled and washed twice with 250 ml of ether. The product solidified and was washed with 100 ml of dichlo-romethane, filtered and dried over P2Os to give 15.3 g of crude material. This material was dissolved in 20 ml of water, and 5J hydrogenated tetrabutylammonium sulfate (7.5 g, 22 mmol) was added. The resulting ion pair product was extracted twice with 200 ml of dichloromethane. The dichloromethane solution was dried (Na2SO4) and concentrated in vacuo. The hydrolysis of acetone oxime was carried out by heating in 120 ml of 2N hydrochloric acid at 60 130 ° C for 4 hours. This solution was concentrated in vacuo from water twice, then from acetonitrile. The product solidified by adding dichloromethane, and was filtered and dried in vacuo to produce 2.5 g of the title compound.

b) Potassium salt of O-sulfomethyl-a-N-t-butoxy-65 carbonyl-L-threonine hydroxamate

Aminoxymethanesulfonic acid (1.14 g, 8.9 mmol) was added to a solution of r-butoxycarbonyl-L-threonine (1.96 g, 8.9 mmol) in 16 ml of water and 4 ml of tetrahydrofuran at 0 C.

658,858

8

The pH was adjusted to 4.5 with KOH at IN, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.87 g, 9.7 mmol) in 8 ml of water was added dropwise. drop. The reaction mixture was stirred at room temperature for 2 hours and, during this time, the pH was maintained between 4 and 4.5 by occasional addition of H2SO4 at IN. The product was ionically coupled with hydrogenated tetrabutylammonium sulfate (3.05 g, 8 mmol) at pH 2.8 and was extracted from the aqueous solution with four 100 ml portions of dichloromethane. The dichloromethane solution was dried (Na2SO4) and concentrated in vacuo to give 4.5 g of product as the tetrabutylammonium salt. This was converted to potassium salt by ion exchange on 150 ml of Dowex 50X (0.7 mEq K® / ml) and, after lyophilization, 2.63 g of the title compound were obtained.

C) O-sulfomethyl-a-N-t-butoxycarbo-nyl-L- (O-methanesulfonylthreonine) hydroxamate tetrabutylammonium salt

To a partial solution of the potassium salt of O-sulfomethyl-aNr-butoxycarbonyl-L-threonine hydroxamate (2.37 g, 6.5 mmol) in 50 ml of dry pyridine at 0-5 ° C under nitrogen was added dropwise 0.8 ml (in excess) of methanesulfonyl chloride. The reaction was stirred at room temperature for 4 hours, then it was concentrated in vacuo. The residue was dissolved in 10 ml of water, and 2.0 g (6 mmol) of tetrabutylammonium hydrogen sulfate at a pH of 2.8 was added. The ionically coupled material was extracted with chloroform. The chloroform was dried and concentrated in vacuo to give 2.6 g of crude product.

D) Potassium salt of [3S- (3a, 4ß)] - 3 - [[(1,1-dimethylethoxy) -carbonyl] amino J-4-methyl-2-oxo-1- (sulfomethoxy) -azetidine

2.6 g (4.0 mmol) of the tetrabutylammonium salt of O-sulfome-thyl-aN -? - butoxycarbonyl-L- (0-methanesulfonylthreonine) hy-droxamate were dissolved in 5 ml of acetone and added dropwise drop to a reflux suspension of 2.2 g of potassium carbonate in 65 ml of acetone. The reflux continued for 3.5 hours and the reaction was cooled, filtered, and concentrated in vacuo. The residue was dissolved in 10 ml of 0.5 M KH2PO4 at pH 5.5, then the pH was adjusted to 2.8. The product was extracted four times with 100 ml portions of dichloromethane, and the combined extract was dried and concentrated in vacuo to give 1.52 of the ionically coupled ß-lactam salt of crude tetrabutylammonium. The potassium salt was obtained by ion exchange through 50 ml of Dowex 50X (0.7 mEq K® / ml) to give, by lyophilization, 0.53 g of crude material, which was then purified by chromatography through 100 ml of HP-20 using water. The appropriate fractions were combined and lyophilized to give 0.245 g of product.

Analysis for C10H17N2O7SK- l, 2HzO:

Calculated: C 32.46 H 5.28 N 7.57 S 8.66%

Found: C 32.52 H 4.76 N 7.43 S 8.30%

E) [3S- (3a, 4ß)] - 1-Sulfomethyl-3-amino-4-methyl-2-oxo-1-azetidine

Potassium salt of [3S- (3a ^)] - 3 - [[(1,1-dimethylethoxy) car-bonyl] -amino] -4-methyl-2-oxo-l- (sulfomethoxy) azetidine (0.245 g , 0.68 mmol) was suspended in 0.5 ml of dichloromethane and 0.5 ml of anisole. The reaction mixture was cooled to 0 ° C, and trifluoroacetic acid (1.0 ml) was added under nitrogen. The reaction mixture was stirred for 1 hour then concentrated in vacuo until a residue was obtained which was evaporated twice from benzene. This residue was triturated with ether, and the ether was allowed to settle to give the desired product as a white solid.

F) Potassium salt of [3S- [3a (Zj, 4ß]] diphenylmethyl ester of acid - 2- [[[1- (2-amino-4-thiazolyl) -2- [[4-methyl -2-oxo-l-

(sulfomethoxy) -3-azetidinyl] -amino] -2-oxoethylidene] amino] oxy] -2-methylpropionic

(Z) -2-amino-a - [[2- (diphenylmethoxy) -1, l-dimethyl-2-oxoethoxy] -imino] -4-thiazole-acetic acid (0.30 g, 0.68 mmol) and 1-hydroxybenzotriazole hydrate (0.10 g, 0.68 mmol) were dissolved in 4 ml of dry dimethylformamide under nitrogen. The reaction was cooled to 0 ° C, and N, N'-dicyclohexylcarbodii-mide (0.14 g, 0.68 mmol) was added in portions. After addition, reaction 5 was stirred at 0 ° C for 1 hour. A solution of

Crude 3-amino-1- (sulfomethoxy) azetidine (about 0.68 mmol) in 10 ml of dimethylformamide and 0.5 ml of N, N-diisopropylethylamine at 0 ° C. The reaction was stirred at 0 ° C for 1 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. By evaporation of the dichloromethane, 0.372 g of crude product was obtained. This product was passed through 30 ml of Dowex 50 (0.7 mEq K® / ml) using water to give, by lyophilization, 0.211 g of crude product contaminated with hydroxybenzotriazole.

G) Dipotassium salt of [3S- [3a (Z), 4ß]] - 2 - [[[1- (2-amino-

4-thiazolyl) -2 - [[4-methyl-2-oxo-1- (sulfomethyl) -3-azetidinyl] -amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic acid

20 The potassium salt of the diphenylmethyl ester of [3S- [3a (Z), 4ß]] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[4- nwthyl-2-oxo-l- (sulfo-methoxy) -3-azetidinyl] -amino] -2-oxoethylidene] amino] oxy] -2-methylpropionic (0.211 g) was dissolved in 1.8 ml of dichloromethane, 0, 5 ml of anisole and 1.5 ml of trifluoroacetic acid, and stirred under nitrogen at 0 ° C for 2 hours. The reaction mixture was concentrated in vacuo and evaporated from benzene twice. The residue was washed with ether: ethyl acetate (1: 1) and with ether: acetonitrile (1: 1) to give a white solid. This was dissolved in 1.0 ml of 0.5 M KH2PO4 and pH 5.5, then the pH was adjusted to 6.5 with KOH at IN, and chromatography was carried out by 40 ml HP-20 with water to give 53 mg of the title compound; melting point 200 ° C, dec.

Analysis for Ci4H17N5OgS2K2 -2.75H20 ":

35 Calculated: 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

[2S- [2a, 3ß (Z)]] - [[3 - [[(2-amino-4-thiazolyl) - (methoxy-40 imino) acetyl] amino] -2-methyl-4-oxo-1 -azetidinyl] oxy] methanesulfonic

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 1, the title compound is prepared as the monopotassium salt in the form of a hygroscopic solid after dissolution in acetonitrile and extraction of acetonitrile under vacuum several times.

IR - S03- (1030 cm-1); ß-lactam (1778 cm-1)

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Analysis for CuH14N507S2K-0- 1CH3CN:

Calculated: 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%

55 Example 3

[2S- [2a, 3ß (R)]] - [[3 - [[[[4-ethyl-2,3-dioxo-1-piperazinyl) car-bonyl] amino Jphenylacetyl] amino J-2-methyl- 4-oxo-1-azetidinyl] -oxo-methanesulfonic

Following the method of Example 1 and substituting a-60 [[(4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] -phenylacetic acid for the thiazole-acetic acid used in part (F) of Example 1, the title compound is obtained as the monopotassium salt in the form of a hygroscopic solid.

IR - S03 ~ (1038 cm- '); ß-lactam (1775 cm-1)

65

Analysis for C20H24N5OQSK- 1,6H20:

Calculated: C 41.53 H 4.74 N12. It S 5.54%

Found: C41.53 H4.46 N 11.13 S 5.61%

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Example 4

(S) -3-Benzyloxycarbonylamino) -4-methyl-2-oxo-1- (sulfomethoxy) -azetidine

Following the procedure of parts of (A) to (D) of Example 1 and substituting the benzyloxycarbonylserine for t-butoxycarbonyl-L-threonine used in part (B), the title compound is prepared as a salt of potassium.

IR - S03- (1025 cm-1); ß-lactam (1775 cm-1).

Example 5

(2a, 3ß) -1-Sulfomithoxy-2- (aminocarbonyl) -3- (((1,1-dimethyl-ethoxy) carbonyl) amino) -4-oxoazetidine a. Erythro-3-hydroxy-dl-aspartic acid

Erythro-3-hydroxy-dl-aspartic acid was prepared from trans-epoxysuccinic acid as described by C.W.

Jones et al. [Can. J. Chem. 47, 4363 (1969)]. Trans-epoxysuc-cinic acid was prepared from fumaric acid as described by G.B. Payne et al. [J. Org. Chem. 24, 54 (1959)].

b. ß-Mäthyl-erythro-3-hydroxy-dl-aspartate

To a suspension of 5.0 g (33.5 mmol) of erythro-3-hydroxy-dl-aspartic acid in 50 ml of dry methanol was added 6 ml of concentrated hydrochloric acid. The mixture was refluxed for 3 hours, cooled to room temperature and evaporated in vacuo. The residue was taken up in 95% ethanol, and the pH was adjusted to 0.8 by addition of pyridine. The white solid obtained was filtered and dried to give 5.2 g (95% yield) of the desired methyl ester having a melting point of 210 ° C, dec.

vs. Erythro-3-hydroxy-dl-asparagine

The above β-methyl aspartate (4.0 g, 24.5 mmol) was dissolved in 40 ml of concentrated ammonia and stirred overnight at room temperature. The reaction mixture was evaporated in vacuo to give a solid which was dissolved in hot water. The pH was adjusted to 5.0 using 6N hydrochloric acid, and the solution was concentrated in vacuo to about 20 ml, then left overnight at 5 ° C. The crystal mass white was collected and dried to give 3.4 g (95% yield) of the desired product having a melting point of 233 ° C, dec.

d. Potassium salt of n-t-butoxycarbonyl-erythro-3-hydroxy-dl-asparagine

7.0 g (47 mmol) of erythro-3-hydroxy-dl-asparagine were suspended in 50 ml of water and solubilized by addition of 3N KOH. This solution was adjusted to a pH of 10.0 and maintained at this pH while adding dropwise a solution of di-t-butylbicarbonate (15.5 g, 71 mmol) in 20 ml of t-butanol. The reaction mixture was stirred at pH 10.0 overnight at room temperature. The t-butanol was extracted in vacuo, and the pH of the aqueous residue was adjusted to 5.0 using 6N HCl. The solution was concentrated in vacuo until a small volume was obtained, then the pH was adjusted to 3.0 (6N HCl). Extraction of the solvent in vacuo gave a solid (20 g) containing the desired product as free acid and approximately in quantitative yield, as well as inorganic salts. A portion (2.9 g) of this solid was taken up in water and KOH diluted to a pH of 6.5 and chromatographed through 100 ml of an HP 20 resin using water and then a acetone-water mixture (1: 9) to give the desired potassium salt as a residue (1.8 g).

e. Tetrabutylammonium salt of aminoxymethanesulfonic acid

Tetrabutylammonium hydrogen sulfate (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 in using diluted KOH. The water was removed in vacuo, and the residue was triturated with methylene chloride. After filtration, the filtrate was dried over sodium sulfate and evaporated to give the desired product as a residue (1.06 g, 2.88 mmol).

f. Potassium salt of O-sulfomethyl-a-n-t-butoxycar-bonyl-erythro-3-hydroxy-dl-asparagine hydroxamate

Potassium salt (0.792 g, 2.77 mmol) was dissolved in water (3 ml) and the pH adjusted to 2.4 (diluted H2SO4). The solution was concentrated in vacuo to obtain a residue which was concentrated from water (2 times), then from benzene (2 times). This residue was dissolved in dry acetonitrile (4 ml) and in dry tetrahydrofuran (8 ml) and cooled until reaching the temperature of 0 "C. To this stirred solution was added 0.424 g (2.77 mmol) of 1-hydroxybenzotriazole monohydrate, followed by the addition of 0.572 g (2.77 mmol) of N, N'-dicyclohexylcarbodiimide The mixture was stirred at 0: C for 2 hours, then the drop was added dropwise tetrabutylammonium salt of the above aminoxymethanesulfonic acid (1.06 g, 2.88 mmol) in 5 ml acetonitrile After this addition the reaction was stirred at 0 ° C for 4 hours The reaction solution was filtered and concentrated in vacuo until a residue is obtained. Water (10 ml) is added, and the residue is triturated at 0 ° C. until it solidifies. The solid was extracted by filtration, and the aqueous filtrate was concentrated until to about 3 ml. The pH was adjusted to 4.0 and the fractionation was carried out on 80 ml of a Dowex 50 (K) ion exchange resin. These were collected and concentrated until a small volume was obtained. The pH was adjusted to 3.4, and the solution was chromatographed on an HP-20 resin to give, after lyophilization, 502 mg (46%) of the desired product in the form of a solid having a melting point of 145: C, Dec

Analysis for C10H18N3O9SK • 0.71H20:

Calculated: 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 '. O-sulfomethyl-a-n-t-butoxycarbonyl-erythro-3-hydroxy-dl-asparagine tetrabutylammonium salt

To a solution of the potassium salt of the preceding asparagine hydroxamate (104 mg, 0.263 mmol) in 1 ml of water, 2.63 ml of tetrabutylammonium hydrogen sulphate was added in a buffer solution of KH2PO4 at 0 , 5M having a pH of 5.5. The solution was concentrated to dryness, and the residue was triturated with methylene chloride. Filtration and evaporation of methylene chloride gave the desired product as a residue (156 mg, hz 0.26 mmol).

g. Potassium salt of (2a, 3ß) -l-sulfomethoxy-2- (aminocarbonyl 1-3 - (((1, l-dimethylethoxy) carbonyl) amino) -4-oxoazetidine

The preceding O-sulfomethyl hydroxamate tetrabutylammonium salt (140 mg, 0.234 mmol) was dissolved in 1.6 ml of dry methylene chloride and stirred with 1 g of molecular sieve (3 Å) overnight. The solution was extracted 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 (0.85 mmol) of triethylamine was added, then 0.08 ml (0.42 mmol) of anhydride was added dropwise. of trifluoromethanesulfonic. The reaction was allowed to warm to -30: C for 1 hour, then 0.06 ml of triethylamine was added. After 5 minutes, the reaction was concentrated in vacuo and the residue was dissolved in 2 ml of acetone. The solution was cooled to 0 ° C, and a solution of 79 mg of potassium perfluorobutane sulfonate in 1 ml of acetone was added. Ether was then added, and the solids were collected by centrifugation. Treatment of the solids by stirring with 2 ml of a Dowex 50 (K) resin in water, filtration and extraction of the water under vacuum gave the desired crude potassium salt containing no amines. Chromatography of this crude potassium salt on an HP-20 resin using water gave 15 mg (20% yield) of the desired potassium salt, after lyophilization, having a melting point of 149 C, dec. and IR (KBR) 1786 cm-1 (ß-lactam carbonyl) and 1696 cm-1 (broad, amide and carbamate carbonyl).

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658,858

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By following the methods described above, the following compounds are prepared:

Monopotassium salt of acid (3S-Ow; .s) - [[(2-amino-4-thiazo-lyl) (methoxyimino) acetyl] amino] -4-methyl-2-oxo-l-azetidinyl] - oxy] methanesulfonic

Monopotassium salt of (3S-ïra "j) acid - [[(2-ammo-4-thiazo-lyl) [(2,2,2-trifluoroethoxy) imino] acetyl] ammo] -4-methyl-2 -oxo-l-azetidinyl] oxy] methanesulfonic

Monopotassium salt of (3S-? Rans) acid - [[(2-amino-4-thiazo-lyl) [(2-amino-2-oxoethoxy) imino] acetyl] amino] -4-methyl-2- oxo-l-azetidinyl] oxy] methanesulfonic

(3S- / rans) acid dipotassium salt - [[(2-ammo-4-thiazolyl) - [(carboxymethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidinyl] - oxy] methanesulfonic

(3S-frans) acid dipotassium salt - [[(2-amino-4-thiazolyl) - [[(l-carboxycyclopropyl) oxy] imino] acetyl] amino] -4-methyl-2-oxo-l -azetidinyl] -oxy] methanesulfonic

Monopotassium salt of [3S- [3a (R), 4ß]] - - [[3 - [(aminophö-nylacetyl) -amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfoni- than

Monopotassium salt of (3S-trans) - [[3 - [(phenylacetyl) -amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid

Monopotassium salt of (3S-trans) - [[3 - [(2-thienylacet-yl) amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid

Monopotassium salt of (3S-trans) - [[3 - [(2,6-dimethoxy-phenyl) acetyl] -amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid

Monopotassium salt of acid [3S- [3a (R), 4ß]] - [[3 - [[[[(amino-carbonyl) -amino] -2-thienylacetyl-amino] -4-methyl-2- oxo-l-azétidi-nyl] -oxy] -methanesulfonic

[3S- [3a (R), 4ß]] - [[3 - [(carboxyphönyl-acetyl) -amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid dipotassium salt [3S- [3a (+), 4ß]] - [[3 - [(phenylsulfo-acetyl) -amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid dipotassium

(3S-trans) acid monopotassium salt] - [[3 - [[((2-amino-4-thiazolyl) -oxoacetyl] amino] -4-methyl-2-oxo-1-azetidinyl] -oxy] methanesulfonic

Monopotassium salt of [3S- [3a (R), 4ß]] - - [[3 - [[[[[2-oxo-3 - [(phenyl-methylene) amino] -1-imidazolidinyl] carbonyl]] amino] -phen-ylacetyl] amino] -4-methyl-2-oxo-1-azetidinyl] oxy] -methanesulfonic

Monopotassium salt of [3S- [3a (Z), 4ß]] - - [[3 - [[2-furanyl- (methoxyimmo) acetyl] amino] -4-methyl-2-oxo-1-azetidinyl] oxy] me-thanesulfonic

Monopotassium salt of [3S (Z)] - - [[3 - [[(2-amino-4-thiazo-lyl) (methoxyimino) acetyl] amino] -2-oxo-l-azetidinyl] oxy] methane -sulfonic

[3S (Z)] acid dipotassium salt - [[3 - [[(2-amino-4-thiazolyl) -

[(l-carboxy-l-methylethoxy) imino] acetyl] amino] -2-oxo-l-azetidin-yl] oxy] methanesulfonic

Monopotassium salt of [3S (Z)] acid - - [[3 - [[(2-amino-4-thiazo-lyl) [(2,2,2-trifluoroethoxy) imino] acetyl] amino] -2- oxo-l-azetidinyl] -oxy] methanesulfonic

Monopotassium salt of [3S (Z)] acid - - [[3 - [[(2-amino-4-thiazo-lyl) [(2-amino-2-oxoethoxy) imino] acetyl] amino] -2- oxo-l-azetidinyl] -oxy] methanesulfonic

Monopotassium salt of [3S- [3a (S), 4ß]] - - [[3 - [[[(aminocar-bonyl) amino] -2-thienylacetyl] amino] -2-oxo-1-azetidinyl] -oxyjmethanesulfonic

[3S- [3a (±), 4ß]] - [[3 - [(ph6nylsulfo-acetyl) -amino] -2-oxo-1-azetidinyl] oxy] methanesulfonic acid dipotassium salt

Monopotassium salt of [3S- [3a (R), 4ß]] - [[3 - [[[[(4-6thyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl] amino acid ] -2-oxo-1 -azetidinyl] oxy] methanesulfonic

Monopotassium salt of [(3S (Z)] - [[3 - [(phenoxyacetyl) -amino] -2-oxo-1-azetidinyl] oxy] methanesulfonic acid

Monopotassium salt of (3S-cw) acid - [[(2-amino-4-thiazolyl) - (methoxyimino) acetyl] amino] -4-methyl-2-oxo-1-azetidinyl] -oxy] even- thanesulfonic

Monopotassium salt of (3S-râ) acid - [[(2-amino-4-thiazolyl) - [(2,2,2-trifluoroethoxy) imino] acetyl] amino] -4-methyl-2-oxo- l-azeti-dinyl] oxy] methanesulfonic

(3S-cw) acid dipotassium salt - [[(2-amino-4-thiazolyl) - - [(carboxymethoxy) imino] acetyl] amino] -4-methyl-2-oxo-1-azetidin-yl ] -oxy] methanesulfonic

(3S-cw) acid dipotassium salt - [[3 - [[((2-amino-4-thiazolyl)] - (l-carboxy-l-methylethoxy) imino] acetyl] amino] -2-oxo- 4-methyl-1-azetidinyl] oxy] methanesulfonic

(3S-cw) acid dipotassium salt - [[(2-amino-4-thiazolyl) [[(l-carboxycyclopropyl) oxy] imino] acetyl] amino] -4-methyl-2-oxo-l- azetidinyl] -oxy] methanesulfonic

Monopotassium salt of (3S-cw) acid - [[2-amino-4-thiazo-lyl) [(2-amino-2-oxoethoxy) imino] acetyl] amino] -4-methyl-2-oxo- l-azetidinyl] oxy] methanesulfonic

Dipotassium salt of [3S- [3a (R), 4ß]] - [[3 - [(carboxyphönyl-acetyl) -amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfontic salt [3S- [3a (R), 4ß]] monopotassium potassium - [[3 - [[[[((4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetyl] amino] -4-methyl-2-oxo-1 -azetidinyl] oxy] methanesulfonic

Monopotassium salt of [3S- [3a (S), 4ß]] - - [[3 - [[[(aminocar-bonyl) -ammo] -2-thienylacetyl] -amino] -4-methyl-2- oxo-l-azetidinyl] -oxy] methanesulfonic

Monopotassium salt of [3S- [3a (R), 4ß]] - [[3 - [(aminophe-nylacetyl) -amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfoni- than

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Claims (14)

658858 2 claims 1. ß-Lactam having a substituent r5 R6 \ / —O — C — SO, H in position 1 and an acylamino substituent in position 3, formula in which R5 and R6 are identical or different and each represents hydrogen, an alkyl, alkenyl, alkynyl, phenyl, substituted phenyl, cycloalkyl, or a heterocycle at 4 , 5, 6 or 7 members, or R5 and R6 form together with the carbon atom to which they are attached a cycloalkyl or a heterocycle with 4, 5, 6 or 7 members, or one of R5 and R6 represents the hydrogen and the other represents an azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, - CHjX ^ —S — X2, —O — X2, or O II —A — C — NX6X7; 20 X represents an azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl) sulfonyloxy, phenyl, substituted phenyl, cyano, -S — X2, or —O — X2; X2 represents an alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl) alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl) carbonyl, or a heteroarylcarbonyl; A represents -CH = CH-, - CH2 — CH = CH—, - (CH2) „-, - (CH2)„ - 0-, - (CH2) „- NH - or - (CH2)„ - S - CH2 -; n is 0.1, 2 or 3; n 'is equal to 1 or 2; and X6 and X7 are the same or different and each represents hydrogen or an alkyl, or X6 represents hydrogen and X7 represents an amino, substituted amino, acylamino or alkoxy, or a salt or an ester thereof. 2. ß-Lactam according to claim 1, wherein R5 and R6 each represent hydrogen. 3. ß-Lactam according to claim 1 having the formula 5. ß-Lactam according to claim 4, wherein one of R3 and R4 is something other than hydrogen. 6. ß-Lactam according to claim 4, in which R3 is hydrogen and R4 is methyl. 7. ß-Lactam according to claim 4, wherein R3 is methyl and R4 is hydrogen. 8. ß-Lactam according to claim 4, wherein R5 and R6 are each hydrogen. 9. ß-Lactam according to claim 4, wherein Rs and R6 are each methyl. 10. ß-Lactam according to claim 4, wherein Rj represents (Z) -2-amino-a - [(1 -carboxy-1 -methylethoxy) imino] -4-thiazole-acetyl. 11. ß-Lactam according to claim 3, wherein R2, R5 and R6 are each hydrogen and one of R3 and R4 represents an alkyl and the other hydrogen. and R6 each represents hydrogen and R4 is methyl. 13. ß-Lactam according to claim 3, wherein R2, R4, and R6 each represent hydrogen and R3 is methyl. 14. ß-Lactam according to claim 1 having the formula rs R ^ -NH-C- §4 -C-R. -N — O — C — S03H or its salt or its ester, in which Rj represents an acyl; R2 represents hydrogen or methoxy; R3 and R4 are the same or different and each represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a heterocycle with 4, 5, 6 or 7 members, or one of R3 and R4 represents l hydrogen and the other represents an azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, —CH2 — Xl5 —S — X2, X, X, O nh2-ch- ■ X §4 -c-r, I 3rS ^ R6 -N — O — C — S03H or a salt thereof, in which R3 and R4 are the same or different and each represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4, 5, 6 or 7 membered heterocycle, or one of R3 and R4 represents hydrogen and the other an azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, carboxyl, —CHÄ, 35 x3 X3 O I 1 II -S-X2, -0-X „-0-C-X4, -S-C-X4, or —A — C — NX6X7; X5 X5 40 -0-X2, -0-C-X4, -S-C-X4, or —A — C — NX6X7; one of the symbols X3 and X4 represents a hydrogen and the other represents a hydrogen, an alkyl, or else X3 and X4, when taken together with the carbon atom to which they are attached, form a cycloalkyl group; 45 X5 is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl) -carbonyl, phenylalkylcarbonyl, (substituted phenyl) alkylcarbonyl, carboxyl, alkoxycarbonyl; aminocarbonyl, (substituted amino) carbonyl, or cyano; and in which the symbols R5, Re, X1; X2 and A are defined as indicated in claim 1. 15. ß-Lactam according to claim 1, a salt of [3S- [a (Z), 4ß]] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [ [4-methyl-2-oxo-1- (sulfo-methoxy) -3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic. 16. ß-Lactam according to claim 14, [3S- (3a, 4ß)] - 1-sulfonw-55 thoxy-3-amino-4-methyl-2-oxo-1-azetidine. x5 X5 where R5, R6, Xj, X2, A, X6 and X7 have the same definition as in claim 1; and one of X3 and X4 represents hydrogen and the other hydrogen or an alkyl, or else X3 and X4, when taken together with the carbon atom to which they are attached, form a cycloalkyl group ; X5 represents a formyl, alkanoyl, phenylcarbonyl, (substituted phenyl) carbonyl, phenylalkylcarbonyl, (substituted phenyl) alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino) carbonyl or cyano. 4. ß-Lactam according to claim 3, wherein R2 represents hydrogen. 65