DD222016A5 - METHOD OF PREPARING NEW BETA LACTAM ANTIBIOTICS - Google Patents

Abstract

The invention relates to a process for the preparation of b-lactams having a substituent of the formula I in which R 1, R 2, R 3, R 4, R 5 and R 6 have the meaning given in the invention, and pharmaceutically acceptable salts thereof. These compounds have antibacterial activity against a number of Gram-positive and Gram-negative bacteria.

Description

r. "·.. - π

10

Title of the invention:

Process for the preparation of new β-lactam antibiotics

Field of application of the invention: 20

The application of the present invention is in the field of drugs, in particular for the treatment of bacterial infections.

25

Object of the invention:

ti

The aim of the invention is to provide new drugs which have efficacy against a number of Gram-negative

30

and gram-positive bacteria.

Explanation of the essence of the invention:

The object of the invention is to provide medicaments

35

to oppose against a number of gram-negative and

Gram-positive bacteria are antibacterially active.

L. , , J

The invention accordingly relates to a process for the preparation of β-lactams of the formula I.

.e R ₁ -NH-C CR-.

¹¹ Ir r I * S \ / 6

NOC-SO ₃ H,. /

or their salts and esters, in which R _{1 is} an acyl radical,

R_ represents a hydrogen atom or a methoxy group,

R and R are the same or different and are hydrogen atoms,

J, fx '

Alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or 4-, 5-, 6- or 7-membered heterocyclic radicals (hereinafter referred to as R ₇ ) or one of the radicals R ₃ and R ₄ is a hydrogen atom and the other is an azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenyläthenyl-, .. 2-Phenyläthinyl or carboxyl group or one of the radicals,

-CH-Χ- ·, - S-X- 1 - 0-X2 / ι 3 ι 3

_ιΛ_ί "" ν cr »ν

I 4 '~ 1 4

^b

ο '' '·

or Il

-A-C-NX, X-

  D /

on

X _{1 represents} an azido, amino (-NH ₃ ), 'hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl) sulfonyloxy, phenyl, substituted phenyl or cyano group or a radical of the formula ^S ~ ^X 2 or "° ~ ^X 2 means

Γ '. -l

X represents an alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl) alkyl, alkanoyl, substituted alkanoyl, phenylcarbonyl, (substituted phenyl) carbonyl or heteroarylcarbonyl radical.

one of X ₃ and X _{4 is} hydrogen and the other is hydrogen or alkyl or X ₃ and X together with the carbon atom to which they are attached form a cycloalkyl radical, X _{5 is} formyl, alkanoyl, phenylcarbonyl, (substituted phenyl) -carbonyl, phenylalkylcarbonyl, (substituted phenyl) alkylcarbonyl, carboxyl, alkoxycarbonyl, Aminocärbonyl- (NH _0-CO-), (substituted amino) carbonyl, or cyano (-C = N) means

A is one of the groups -CH = CH-, -CH ₀ -CH = CH-, - (CH ₀ ) -,

) ^ O-, - (CH ₂ J _{n is} TNH- or - (CH 2 rS-CH ^, η is 0, 1, 2 or 3, n ¹ is 1 or 2 ,.

X and X_ are the same or different and each one b /

Represent hydrogen atom or an alkyl radical or

X _{r is} a hydrogen atom and X is an amino, substitub /

means amino, acylamino or alkoxy group.

R ₁ - and R _{fi are the} same or different and are hydrogen atoms.

Alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or 4-, 5-, 6- or 7-membered heterocyclic radicals or R ₅ and R _g together with the carbon atom to which they are attached , a cycloalkyl radical or a 4-, 5-, 6- or 7-membered heterocyclic radical, or one of the radicals R ₁ - and R _{f is} a hydrogen atom and the other is an azido, halomethyl, dihalomethyl, trihalomethyl, Alkoxycarbonyl, 2-phenyläthenyl-, 2-Phenyläthinyl- or carboxyl group or one of the radicals

Il -CH ^ X ₁ , -SX ₀ , -O-X _o or -AC-NX _C X

which is characterized in that a compound of the formula

NH-CH-

in which R ₃ , R ₄ , R ₅ and R _{g have} the meanings given above and A _{1 represents} an amino-protecting group,

to a product of formula 10

R ₂ R4

A, NH ι C C R ^

N-O-CR _C .R _C -SO- ₁ H ^{5 6 3}

CN-O-CR _C .R _C SO- ₁

<f ^{5 6 3}

cyclized, wherein R- represents a hydrogen atom, the product obtained is optionally methoxylated by treatment with a halogenating agent and a methoxylating agent, the amino-protecting group is split off and the resulting compound in which R _{1 is} a hydrogen atom, optionally acylated.

J 25 The invention also relates to the said process with the particularity that R _{2 is} a hydrogen atom.

Furthermore, the invention relates to the said method with the special feature, is.

Special feature that one of the radicals R and R. no water

Γ' Π

         - 4 -

^ ₁ -NH-CH-CR

C. NH-O-CR ₅ R ₆ -SO ₃ H

_t in which R, R, R ₅ and R have the meanings given above and A _{1 represents} an amino-protecting group,

to a product of formula 10

, R ₂ R ₄ ¹

ΑΧΎΤΤ / Ί η p

N-O-CR ₁ -R 1 -SO _n H

, -R - SO 5 6

cyclized, wherein R- is a Wasserstoffatonu / the product obtained is optionally methoxylated by treatment with a halogenating agent and a methoxylating agent, the amino-protecting group cleaves off and the resulting compound in which R is a hydrogen atom, optionally acylated. ν

The invention also relates to said process with the particularity that R- is a hydrogen atom.

Furthermore, the invention relates to said method with the particularity that one of the radicals R and R is not a hydrogen atom.

^Γ - 5 -. "

Further, the invention relates to the said method with the "special feature that R- is a hydrogen atom and R. is a methyl group.

Furthermore, the invention relates to said method with the particularity that R-, a methyl group and R. is a hydrogen atom.

Furthermore, the invention relates to said method with the particularity that R _c and R, are hydrogen atoms.

Furthermore, the invention relates to said method with the particularity that R ₅ and R, are methyl groups.

Further, the invention relates to said process with the particularity that R _{1 is} the group (Z) -2-amino-a - [(1-carboxy-1-methylethoxy) -imino] -4-thiazoleacetyl.

Furthermore, the invention relates to said method with the particularity that R_, R _c and R ₁ , each hydrogen bb

and one of R and R is an alkyl group and the other is a hydrogen atom.

Furthermore, the invention relates to said method with the particularity that R ₃ , R ₃ , R ₅ and R · are each hydrogen atoms and R _{4 is} a methyl group.

Furthermore, the invention relates to the said method with the particularity that R ₃ , R ₄ , R ₅ and R _{g are} each hydrogen atoms and R _{3 is} a methyl group.

Furthermore, the invention relates to said method with. the peculiarity that R .. is a hydrogen atom.

Furthermore, the invention relates to said method with the particularity that R _{1 is} an amino protecting group.

L J

Furthermore, the invention relates to said process with the particularity that the product [3S- [3a (Z), 4ß]] -2- [[[1- (2-amino-4-thiazolyl) -2 - [4] methyl 2-oxo-1- (sulfomethoxy) -3-azetidinyl] amino] -2-oxoethylidyl] amino] oxy] -2-methylpropionic acid.

Furthermore, the invention relates to said method with

the particularity that the product [3S- (3ct, 4ß)] - 1-sulfomethoxy-

3-amino-4-methyl-2-oxo-1-azetidine. 10

Definitions and designations permitted in the description of the β-lactams of the invention are given below. These definitions refer to terms used in the logon text (unless they are particularly limited in some cases), either individually or as part of larger groups.

The terms "alkyl" and "alkoxy" refer to; on branched and unbranched rests. Radicals of 1 to 10 carbon atoms are preferred.

The terms "cycloalkyl" and "cycloalkenyl" refer to cycloalkyl and cycloalkenyl radicals having 3, 4, 5, 6 or 7 carbon atoms

 25

The term "substituted alkyl" refers to alkyl radicals having at least one azido, amino (-NH ,,), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, ⁽³ ^ tuiertes substitutable phenyl) oxy, R ₇ oxy, mercapto, alkylthio, phenylthio, (substituted phenyl) thio, alkylsulfinyl or alkylsulfonyl group are substituted.

Γ - 7 - Π

The terms "alkanoyl", "alkenyl", "alkenyl" and "alkynyl" refer to branched and unbranched radicals. These radicals preferably have 2 to 10 carbon atoms.

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

The term "protected carboxyl group" refers to carboxyl groups which have been esterified with common acid protecting groups. These radicals are known in the art; see.

For example, U.S. Patent 4,144,333. Preferred carboxyl protecting groups are the benzyl, benzhydryl, tert-butyl, p-methoxybenzyl and p-nitrobenzyl esters.

The term "substituted phenyl" refers to phenyl groups having 1, 2 or 3 amino (-NH ₂ ), tertiary, hydroxyl, trifluoromethyl, alkyl (having 1 to 4 carbon atoms), alkoxy (having 1 to 4 carbon atoms ) or carboxyl groups.

The term "4-, 5-, 6- or 7-membered heterocycle" (referred to as "R _i7 ") refers to substituted and unsubstituted aromatic and non-aromatic radicals having at least one nitrogen, oxygen or sulfur atom. Examples of substituents are the oxo group (= 0), halo, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl (having 1 to 4 carbon atoms), alkoxy (having 1 to 4 carbon atoms), alkylsulfonyl , Phenyl, substituted phenyl, 2-furylimino- _{0 rH} _ _N _

tLJ "")

Benzylimino and substituted alkyl groups (having 1 to 4 carbon atoms in the alkyl moiety). One type of "4-, 5-, 6- or 7-membered heterocycle" is the "heteroaryl" radical. The term "heteroaryl" refers to those 4-, 5-, 6- or 7-membered heterocycles which are aromatic. Examples of heteroaryl radicals are substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl,

L - J

^Γ -. 8th -

! ι 1,2,3-triazolyl, 1, 2,4-triazolyl, imidazolyl, · thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl and tetrazolyl groups. Examples for. non-aromatic heterocycles, ie, fully or partially saturated hetero cyclic groups are substituted and unsubgtituierte \ Acetidinyl-; Oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl and hexahydroazepinyl

  '*' '' i

groups. <

Specific examples of substituted 4-, 5-, 6- or 7-membered heterocycles are the 1 ^ alkyl-3-azetinyl, 2-OXO-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-1-imidazolidinyl, 3-Benzylimino-2-oxo-1-imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl, 3-phenyl (or substituted phenyl) -2-OXO-1-imidazolidinyl, 3-benzyl-2 -oxo-1-imidazolidinyl, 3- (2-aminoethyl) -2-OXO-1-imidazolidinyl, 3-amino-2-OXO-1-imidazolidinyl, 3 - [(alkoxycarbonyl) amino] -2- oxo-iimidazolidinyl, 3- [2 - [(alkoxycarbonyl) amino] ethyl] -2-oxo-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2, oxo-3-oxazolidinyl, 4 -Hydroxy-6-methyl-2-pyrimidinyl-, 2-0xo-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 radicals of the formula -NY ₁ Y-, wherein Y _{1 is} a hydrogen atom, an alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl) alkyl radical and Y _{3 is} an alkyl, phenyl -, substituted phenyl, phenylalkyl, (substituted phenyl) alkyl, hydroxy, cyano, alkoxy, phenylalkoxy or amino (-NH_) represent. · · · · '

The term "substituted alkanoyl" includes compounds

'"of the formula (substituted alkyl) -C-, wherein" substituted

Alkyl "as defined above, and Phenylalkanoylreste.

The term "acyl radical" refers to any one by removal of the hydroxyl group from an organic acid, i. a carboxylic acid derived organic radicals. Certain acyl radicals are of course preferred, but the invention is not limited thereto. Examples of suitable acyl radicals are those which have been used in the past for the acylation of β-lactam antibiotics including 6-aminopenicillanic acid and its derivatives and 7-aminocephalosporanic acid and its derivatives, cf. for example, cephalosporins and penicillins, published by Flynn, Academic Press (1972), DE-OS 2,716,677, BE-PS 868,994, US Patents 4,152,432, 3,971,778 and 4,172,199 and British Patent 1,348,894.

The following list of acyl radicals serves to further clarify the term "acyl radical"; but the invention is not limited thereto. Specific examples are: (a) Aliphatic radicals of formula 0

R is an alkyl, cycloalkyl, alkoxy, alkenyl,

Cycloalkenyl, cyclohexadienyl or an alkyl or alkenyl radical substituted by at least one halogen atom, cyano, nitro, amino, mercaptoalkylthio or cyanomethylthio group;

(b) Carbocyclic aromatic radicals of the formulas

L J

^Γ . - 10 -

R ^ -L-R, Ο

b ^ CU ^ α μ

CH ₂ -OC-,

0 I!

S-CH ₂ -C-

in which η is 0, 1, 2 or 3, R, R and R independently of one another are hydrogen or halogen atoms or hydroxyl, nitro, amino, cyano or trifluoromethyl groups or alkyl radicals having 1 to 4 carbon atoms, alkoxy radicals with 1 to 4 carbon atoms or aminomethyl groups, and R represents an amino or hydroxyl group, a carboxyl salt, a protected carboxyl group, a formyloxy group, a sulfo or sulfoamino salt, an azido group, halogen atom, hydrazino, alkylhydrazino, phenylhydrazino or [(alkylthio ) thioxomethyl] thio group.

Preferred carbocyclic aromatic acyl radicals have the formulas

O HO- / V ^CH 2 - "- '

10

0 Il

H ₂ -C,

CH ₀ NH ₀

15 20

(R x is preferably a carboxyl or sulfo salt) and

Il

CH-C-I

^R e

(R is preferably a carboxyl or sulfo salt).

25 30 35

(c) Heteroaromatic radicals of the formulas

P _f - (CH ₂ ) _r

0 Il

R ^ -CH-C- ^r I

^R e

R _f -

Il

O Il

R _{f is} -S-CH ₂ -C-,

OO il il R _f -C-C-

in which η is 0, 1, 2 or 3, R is as defined above and R _{f is} a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring (heteroaryl ring) of 1, 2, 3 or 4 (preferably 1 or 2) represents nitrogen, oxygen or sulfur atoms. Examples of heterocyclic rings are the thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl groups. Examples of substituents are halogen atoms, hydroxyl, nitro and amino groups, protected amino groups, cyano and trifluoromethyl groups, alkyl radicals having 1 to 4 carbon atoms, alkoxy radicals having 1 to 4 carbon atoms or the group of the formula

O-

HOOC-CH-CH ₀ -OC-NH I ²

Preferred heteroaromatic acyl radicals are those radicals of the above formulas in which R, a 2-amino-4-thiazolyl, 2-amino-5-halogeno-4-thiazolyl, 4-aminopyrimidin-2j-yl, 5-amino 1, 2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl or 6-aminopyridin-2-yl group.

(d) [[(4-Substituted-2,3-dioxy-1-piperazinyl) -carbonyl] -amino] -aryl-acetyl radicals of the formula -

0 0 -. '.

 M II / V -C-CH-NH-C-N

^R g

in which R represents an aromatic radical (including carbocyclic aromatics, such as those of the formula

"R_ ' ^P -

and heteroaromatic radicals having the definition of R _f ) and R, an alkyl radical, substituted alkyl radical (in which the alkyl radical is substituted by at least one halogen atom, cyano, nitro, amino or mercapto group), arylmethylene amino radical (ie -N = CH- R, wherein R is as defined above), arylcarbonylamino radical (ie

0; -NH-CR _g ,

wherein R is as defined above) or alkylcarbonylamino radical.

Preferred [[(4-substituted-2,3-dioxo-1-piperazinyl) -carbonyl] -amino] -aryl-acetyl radicals are those in which R represents an ethyl, phenylmethyleneamino or 2-furylmethyleneamino group.

(e) (Substituted Oxyirninb) -arylacetyl radicals of the formula

O Il.

-C-C = N-O-R

 I 1

in which R is as defined above and R. is a water

g!

atom, R _fi , an alkyl, cycloalkyl or alkylaminocarbonyl, an arylaminocarbonyl (ie

0 -C-NH-R,

where R is as defined above i; t) or substituted g

Represents an alkyl radical (wherein the alkyl radical contains at least one halogen atom, cyano, nitro, amino, mercapto or alkylthio group, an aromatic radical (as defined by R), a carboxyl group (including the salts thereof), an amido, alkoxycarbonyl , Phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxypnosphinyl,

L J

~ ι

¹⁰

Substituted dihydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl or dialkoxyphosphinyl).

Preferred (substituted oxyimino) arylacetyl radicals are those in which the radical R is the 2-amino-4-thiazolyl group. Also preferred are those groups in which R. is a methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl group.

(f) (acylamino) arylacetyl radicals of the formula

0'0

U Il ι

-C-CH-NH-C-R • I J

in which R is as defined above and R. is a radical

g D

the formula 'ι.

20

25

an amino, alkylamino, (cyanoacyl) amino. Amido, alkylamido or (cyanoalkyl) -amido group or one of the radicals of the formulas

NH

-CH-CH ₂ -C -NH-CH ₃ ,

30

represents.

Preferred (acylamino) -aryl-acetyl radicals of the above formulas are those in which R. represents an amino or amido ^ O group. Preference is further given to those compounds in which R is a phenyl or 2-thienyl group.

(g) [[[3-Substituted-2-oxo-1-imidazolidinyl] carbonyl] amino] arylacetyl radicals of the formula f?

OOC II / I <s \

-C-CH-NH-C-NN-R

in the R as defined above and R _{1 is} a hydrogen

g k

atom, an alkylsulfonyl or arylmethylene amino group O

(i.e., -N = CH-R, wherein R is as defined above), -C-R g << g in

(wherein R represents a hydrogen atom, an alkyl or a halogen-substituted alkyl radical), an aromatic radical (as defined above by R), an alkyl or substituted alkyl radical (wherein * the alkyl radical having at least one * halogen,, cyano, nitro -, amino or mercapto group may be substituted). 30

Preferred [[[3-substituted-2-oxo-1-imidazolidinyl] -carbonyl] -amino-aryl-acetyl radicals of the above formulas are those in which R is a phenyl or 2-thienyl group. Also preferred are those compounds in which R represents a hydrogen atom, a methylsulfonyl, phenylmethyleneamino or 2-furylmethyleneamino group.

L J

The terms "salt" and "salts" refer to basic salts with inorganic and organic bases. Such 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 with organic bases such as dicyclohexylamine, benzathine, N-methyl-D-glucamine and hydrabamine salts, salts with Amino acids, such as arginine and lysine. The non-toxic pharmaceutically acceptable salts are preferred, but other salts are also valuable, for example, to recover and purify the products.

The salts are prepared in the usual manner by reacting the products in the form of the free acid with at least one equivalent of a suitable base, provided that

¹ ^ the desired cation is present in a solvent or medium in which the salt is insoluble or in water, the water is then preferably removed by freeze-drying. By neutralizing the salts with an insoluble acid, for example a cation exchange

^ Resin in the H form (such as a polystyrene sulphonic - acid resin such as Dowex 50) or with an aqueous acid and extraction with an organic solvent such as ethyl acetate or Dichlorme than can the free acid form can be obtained and, if desired, in a other salt are converted.

ß-lactams with a substituent of the formula

^R 5 _N / ^R 6

-0-C-SO ₃ H

(or a salt thereof) in the

1-position and an amino or acylamino substituent in the 3-position contain at least one asymmetric center, namely the carbon atom (in the 3-position of the β-lactam nucleus), to which the amino or acylamino substituent bound.

that is. The invention is directed to those β-lactams as described above in which the stereochemistry at the 3-position asymmetry center of the β-lactam ring is the configuration of the 6-position carbon of the naturally occurring penicillins {e.g. penicillin G) and the configuration of the carbon atom in 7-position of the naturally occurring cephamycins (for example, cephamycin C) corresponds.

In the preferred β-lactams of formula I, the structural formulas were drawn so that the stereochemistry is seen at the asymmetric center in the 3-position.

The invention also includes racemates which contain the β-lactams described above.

ß-lactams with a substituent of the formula

Rr ^R C

5 _S / -0-C-SO ₃ H

(or a salt thereof) at the 1-position of the β-lactam nucleus and an acylamino substituent at the 3-position of the β-lactam nucleus are effective against a variety of Gram-negative and Gram-positive organisms. The substituent of the formula

-0-C-SO ₃ H

(or a salt thereof) is of crucial importance for the activity of the compounds of the invention.

The compounds of the invention are useful as medicaments for the treatment of bacterial infections, including urinary tract infections and respiratory tract infections in mammals, such as domestic animals such as dogs, cats, cows and whistles, as well as in humans.

L j

^Γ '- 18 -

  For the treatment of bacterial infections in mammals, the compounds of the invention are used in an amount of about 1.4 mg / kg / day to about 350 mg / kg / day; preferably from about 14 mg / kg / day to about 100 mg / kg / day. All modes of administration which have been used in the past for the administration of penicillins and cephalosporins are also contemplated for the new group of β-lactams of the invention.

_x These include oral, intravenous and intramuscular administration and suppository administration. 10

The β-lactams of the invention can be prepared from an amino acid of formula II. , .

NH ₀ -CH-CR ^ (H)

2, 3

OH.

The amino group is first provided with a conventional protecting group, for example a tert-butoxycarbonyl, benzyloxycarbonyl or o-nitrophenylsulfenyl group, to give a compound of formula III.

₉ c OH _ '

ANHCH ^ CR

OH

/ C 0 "

In the formula III, "A" means a nitrogen protecting group as throughout the description.

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

'.' , '. ','

^Γ . · - 19 -

The reaction proceeds in the presence of a coupling agent such as i-ethyl-3- (3-dimethylaminopropyl) carbodiimide or dicyclohexylcarbodiimide to give a compound of formula V.

"1""Y"" ^Λ 3 _{v)

I ^R 5v ^ 6 / C NH-O-C-SO ^ H.

The hydroxyl group of the compound of formula V or a salt thereof is then converted to an leaving group. For example, a common reagent such as methanesulfonyl chloride is used (methanesulfonyl will be referred to as "Ms" hereinafter).

The fully protected compound has the formula VI

_(VI)

^ -HH-CH-CR ₃

, c _NH _o ^ -C-SO ^ H,

25 O ^

(or a salt thereof) and is cyclized by treatment with a base such as potassium carbonate. This reaction is preferably conducted in an organic solvent such as acetone under reflux to give a compound of the formula VII or a salt thereof.

₁ 35

• §4 A ₁ -NH-CH-CR ₇ (VII)

11 l

1 L /% / C-; NO-C - SO ₃ H

L J

In another embodiment, the cyclization of the compound of the formula V can also be achieved by. first, the hydroxyl group is converted to a leaving group. Treatment of the compound of formula V (or a salt thereof) with triphenylphosphine and diethyl azodicarboxylate or carbon tetrachloride and triethylamine gives a compound of formula VII.

The two-called ^ method for ring closure of a compound ¹ der.Formel V ^ yield an inversion of the stereochemistry at the the radicals R, un'd R. bonded carbon atom.

The deprotection of the 3-amino substituent of the compound of formula VII can be achieved by methods known in the art. For example, when the protecting group is a tert-butoxycarbonyl group, trifluoroacetic acid and anisole can be used to deprotect. When the protective group is a benzyloxycarbonyl group, catalytic hydrogenation can be used, for example, with palladium on activated carbon. When the protecting group is an o-nitrophenylsulfenyl group, p-toluenesulfonic acid may be used in conjunction with p-thiocresol. The deprotected compound has the formula VIII

,

• i-4

T -> NH ₀ -CH CR., _D (VIII)

² II ' ^3R 5, / ^R 6'

/ _/ C -N-O-C - SO ₃ H,

... (or a salt thereof) which is a key intermediate for the preparation of the compounds of the invention.

-ή

Known acylation methods can be used to convert the compound of formula VIII into a corresponding compound of formula IX or a salt thereof.

L ... - '. , ''. 'J

Γ ". 2Λ -

R-NH-CH ₃ CR

  1 JR .R,

Specific examples of such processes are the reaction with a carboxylic acid (R ₁ -OH) or a corresponding carboxylic acid halide or anhydride. The reaction with a carboxylic acid proceeds best in the presence of a carbodiimide, such as dicyclohexylcarbodiimide, and a substance capable of generating in situ a reactive intermediate, such as N-hydroxybenzotriazole or 4-dimethylaminopyridine. In those instances where the acyl radical (R-) carries a reactive functional group, such as an amino or carboxyl group, it may be necessary to first protect this functional group, then carry out the acylation reactions, and finally the resulting product from the protecting group to free.

The products of formula I in which R _{2 is} a methoxy group can be prepared from the corresponding compounds of formula VII in which A is a benzyloxycarbonyl group. By halogenation, preferably chlorination _; of the amide nitrogen of the compound of formula VII, a compound of formula X is obtained (or, a salt thereof).

0 Cl R

^ _- J) -CH ₂ -OCN-CH CR ₃ (χ)

r & ' ^l 3'

The reactants and methods of N-chlorination of amides are known in the art. Examples of reactants are tert-butyl hypochlorite, sodium hypochlorite and chlorine. The reaction can be carried out in an organic solvent.

L J

r ''. ·. ί

- 22 -

for example, in a lower alkanol such as methanol, and in a two-phase solvent system such as water / methylene chloride in the presence of a base such as sodium borate decahydrate. The reaction is preferably carried out at reduced temperature.

Reaction of a compound of formula X with a methoxy-lating agent, such as an alkali metal methoxide, yields a compound (in combination with its enantiomers, when R 1 and R 3, are the same or when the compound of formula X is a

  ''. ' 'ι

Racemate), Formula XI (or a salt thereof).

. §4 "^ V-CH _n -OC-NH-C CR ₃ - (XI)

-NOC-Io ₃ H,

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

In another embodiment, a compound of formula VII, ¹ in which A ₁ is benzyloxycarbonyl may be converted into a compound of formula XI by using a one-step process. The methoxylating agent may be first mixed with a compound of formula VII and the N-chlorinating reagent added to the reaction mixture. , · · ·

The conversion of a compound of formula XI to the desired product of formula I may be carried out as described above for the conversion of an intermediate of formula VII to a compound of the invention.

r · ~ ι

The starting compounds of formula II can be readily obtained by known methods; see. Synthesis (1979), p. 216 and J. Org. Chem. 44 (1979), p. 396.7.

Embodiment: ·.

example 1

Dipotassium salt of [3S- [3a (Z), 4β]] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [- (methyl) oxo-i- (sulfomethoxy) -3-] azetidinyl] - amino] -2-oxoethylidene] -amino] oxy] -2-methylpropionic acid

A) Aminoxymethanesulfonic acid

A suspension of 0.8 g (20 mMo.1) of 60% mineral oil dispersion of sodium hydride in 16 ml of anhydrous dimethylsulfoxide is combined with 1.46 g (20 mmol) of acetone-bisimine. Thereafter, 3.94 g (2OmMoI) sodium bromomethanesulfonate are added batchwise. The reaction mixture is heated for 4 hours under nitrogen to 90 to 95 ° C, then cooled and washed twice with 2 50 ml of diethyl ether. The product solidified, is washed with 100 ml of dichloromethane, filtered and dried over Ρ ₂ °. ₅ Yield: 15.3 g of crude product which is dissolved in 20 ml of water and treated with 7.5 g (22 mmol) of tetrabutylammonium hydrogen sulfate.

The resulting ion-paired product is extracted twice with 200 ml of dichloromethane. The dichloromethane solution is dried over sodium sulfate and evaporated under reduced pressure. The acetone oxime is then hydrolyzed by heating in 120 ml of 2N HCl at 130 ° C. for 4 hours. The resulting solution is evaporated under reduced pressure twice from water and then from acetonitrile. The product is precipitated by addition of dichloromethane, filtered and dried under reduced pressure. Yield: 2.5 g of the title compound.

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B) Potassium salt of 0-sulfomethyl -α -N- t -butoxycarbonyl-L-threonine-hydroxamate

A solution of 1.96 g (8.9 mmol) of tert. -Butoxycarbonyl-L-threonine in 16 ml of water and 4 ml of tetrahydrofuran is added at 0 C with 1.14 g (8.9 mmol) Aminoxymethänsulfonsäure. The pH is adjusted to 4.5 with 1N KOH and then 1.87 g (9.7 mmol) of 1-ethyl-2- (3-dimethyl-aminopropyl) carbodiimide hydrochloride in 8 ml of water are added dropwise. The reaction mixture is stirred for 2 hours at room temperature, maintaining the pH at 4 to 4.5 by occasionally adding 1N H-SO. The product is then ion-paired with the product by adding 3.05 g (8 mmol) of tetrabutylammonium hydrogensulfate at pH 2.8, and the product is extracted from aqueous solution with 4 ^{l of} 100 ml of dichloromethane. The resulting dichloromethane solution is dried over sodium sulfate and evaporated under reduced pressure. Yield: 4.5 g of product as tetrabutylammonium salt. This is converted to the potassium salt by ion exchange on 150 ml Dowex 50 X (0.7 meq K / ml). After lyophilization, 2.63 g of the title compound are obtained.

C) Tetrabutylammonium salt of O-sulfornethyl-aNt-butoxycarbonyl-L- (O-methanesulfonylthreonine) hydroxamate

A partial solution of 2.37 g (6.5 mmol of potassium salt of O-sulfomethyl-1-aN-tert-butoxycarbony 1-L-t'hreonine hydroxamate in 50 ml of anhydrous pyridine is added at 0 to 5 C under nitrogen The reaction mixture is stirred for 4 hours at room temperature and then evaporated under reduced pressure, the residue is dissolved in 10 ml of water and treated at pH 2.8, with 2.0 g of sodium hydroxide solution. The ion-paired product is extracted with chloroform, the chloroform solution is dried and evaporated under reduced pressure to give 2.6 g of crude product.

Γ '. - 25 - '-η

D) Potassium salts of [3S- (3α, 4β)] -3 - [[(1,1- dimethylethoxy) carbonyl] amine o] -4-methyl-2- oxo-1 - (sulf omet hoxy) azetidine

2.6 g (4.0 mmol) of tetrabutylammonium salt of ~-sulfomethyl-aN-tert-butoxycarbonyl-L- (O-methanesulfonylthreonine) hydroxamate are dissolved in 5 ml of acetone and added dropwise to a refluxing suspension of 2.2 g of potassium carbonate in 65 ml of acetone. The mixture is refluxed for a further 3.5 hours, then cooled, filtered and evaporated under reduced pressure. The residue is dissolved in 10 ml of 0.5 M KH ₃ PO ₄ of pH 5.5 and the pH is adjusted to 2.8 * The product is extracted four times with 100% dichloromethane, the combined extracts are dried and placed under evaporated under reduced pressure.

Yield: 1.52 g of crude, ion-paired tetrabiylammonium-β-lactam salt. The potassium salt is obtained by ion exchange on 50 ml Dowex 50 X (0.7 meq K ⁺ / ml). After lyophilization, 0.53 g of crude product are obtained, which is further purified by chromatography on 100 ml of HP-20 with water as eluent. The appropriate fractions are combined and lyophilized. Yield: 0.245 g.

25 Analysis: For C 32, 46 5 K.1, 2 H, 28 H ₂ O: N 7, 57 S 8,66 Found .: 32 52 4 , 76 7, 43 8.30 E) [3S- (3α, 4SS) 3-1-Suifomethyl-3-ami no-4-methy1-2-oxo-1- 30 azetidin

0.245 g (0.68 mmol) potassium salt of [3S- (3a, 4β9] -3 - [{(1,1-dimethylethoxy) carbonyl] amino] -4-methyl-2-oxo-1- (sulfomethoxy) azetidin are suspended in 0.5 ml of dichloromethane and 0.5 ml anisole. The mixture is then cooled to 0 ⁰ C under nitrogen and treated with 1.0 ml trifluoroacetic acid.

 ) The reaction mixture is stirred for 1 hour and then evaporated under reduced pressure. The residue is evaporated twice from benzene. Thereafter, the residue is digested with diethyl ether. The ether is decanted, with. the desired product is obtained as a white solid.

F) Potassium salt of [3S- [3a (Z), 4β]] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[4-methyl-2-oxo-1- (sulfomethoxy ) -3-azetidinyl] amino] -2-oxoäthyliden] amino] oxy] -2-methylpropionsäurediphenylmethyJester

0.30 g (0.68 mmol) of (Z) -2-amino-a - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] -imino] -4-thiazoacetic acid and 0, 10 g (0.68 mmol) of 1-hydroxybenzotriazole hydrate are dissolved under nitrogen in 4 ml of anhydrous dimethylformamide. The solution is cooled to 0 C and treated batchwise with 0.14 g (0.68 mmol) of N, N ¹ -Dicyclohexylcarbodiimid. After the addition, the reaction mixture is stirred at 0 C for 1 hour. The mixture is then treated with a solution of about 0.68 "mmol of the crude 3-amino-1- (sulfomethoxy) azetidine prepared above in 10 ml of dimethylformamide and 0.5 ml of Ν, Ν-diisopropylethylamine at 0 ° C . stirred for 1 hour at 0 C and then for about 15 hours at room temperature then the solution is filtered and evaporated the F.iltrat under reduced pressure and the ^{^;} -. residue is dissolved in 50 ml Dichlofmethan and washed with 2 ml of water After evaporation. of the dichloromethane is obtained 0.372 g of crude product which is run through 30 ml of Dowex 50 (0.7 meq K ⁺ / ml) with water as eluent After lyophilization 0.2: 11 g of crude product is obtained which is contaminated with hydroxybenzotriazole.

L. · J

^Γ . * - 27 -

G) dipotassium salt of [3S- [3 α (Z), 4ß]] - 2- [[[1 - (2-araino-4-

thiazolyl) -2 - [[4-methyl- 2-oxo-1- (sulfomethoxy) -3- acetyldinyl] amino] -2-oxoethylidyl] amino] oxy] -2-methylpropionic acid e

'

0.211 g of potassium salt of [3S- [3a (Z), 4β]] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[4-methyl-2-oxo-1- (sulfomethoxy ) -3-azetidinyl] amino] -2-oxoethylidyl] -amino] -oxy] -2-methylpropionic acid diphenylmethyl ester are dissolved in 1.8 ml of dichloromethane, 0.5 ml '.

Anisole and 1.5 ml of trifluoroacetic acid and stirred under nitrogen at 0 ° C for 2 hours. Then the reaction mixture is evaporated under reduced pressure and then evaporated twice from benzene .. The residue is treated with diethyl ether and ethyl acetate in the ratio 1: 1 and then with Diethyl ether and acetonitrile in a ratio of 1: 1 to give a white solid is obtained- This is dissolved in 1.0 ml of 0.5 M KH_PO. Solution of pH 5.5, with 1 N KOH to pH 6.5 and chromatographed through 40 ml of HP-20 with water as the eluent. Yield: 53 mg of the title compound of ^; F. 200 ⁰ C (dec.).

Analysis for C ₁₄ H 7N ₅ O ₉ S ₂ K ₂ .2.75 H ₃ O: <

C H N S: 28.44 3.84 11.85 10.84

F .: 28.32 3.36 11.90 10.37.

Example 2

[2S- [2g, 3R (Z)]] - [[3 - [[(2-amino-4-thiazolyl) - (methoxyimino) acetyl] amino] -2-methyl-4-oxo-1-azetidinyl ] oxy] methanesulfonic

Example 1 is repeated with the change that in Part

(F) used thiazole acetic acid by an equimolar amount of (2) -2-amino-a - [(methoxy) -imino] -4-thiazole acetic acid

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Γ - 28 -, 'Π

is replaced. After repeated dissolution in acetonitrile and removal of the acetonitrile under reduced pressure, the title compound is obtained as a monopotassium salt in the form of a hygroscopic solid.

IR: SO ₃ "(1030 cm ^-1 ); β-lactam (1778 cm ^-1 )

Analysis for C ₁ → ₁₄ N ₅ O ₇ S ₃ K.0, ICH ₃ CN

C H N S

! 0 calculated: 38.11 4.82 15.92 12.56

gef.V 37,94 5,36 15,92 12,56

Example 3

[2S- [2g, 3β (R)] '] - [ [3- [ [ ^: [ [ '(4-Xthyl-2,3-dioxo-1 -piperazinyl) carbonyl] amino] -phenyl! acetyl] amino] 2-methyl-4-oxo-1-azetidinyl-PJ-oxy-methanesulfonic acid

Example 1 is repeated with the change that in part (F) the thiazole acetic acid used is replaced by α - [[(4-x-thyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] phenylacetic acid. The title compound is obtained as a potassium salt in the form of a hygroscopic solid, ν

IR spectrum: SO ₃ "(1038 cm" ¹ )? β-lactam (1775 cm ^-1 ).

Analysis for C ₂₀ H ₂₄ N ₅ O ₉ SK.1.6 H ₃ O:

About: 41 C 4 H 1 2 N 1 5 S 30 Found .: 41 , 53 4 , 74 1 1 ,1 3 '5 , 54 , 53 , 46 ,1 , 61

L ·. .. 'j

Γ _.29 -

Example 4

(S) -3-Benzyloxycarbonylamine o) -4-methyl- 2-oxo-1- (sulfomethoxy) -azetidine 5

Example 1 Parts (A) to (D) are repeated except that the tert-butoxycarbonyl-L-threonine used in part (B) is replaced by benzyloxycarbonylserine. The title compound is obtained as the potassium salt. 10

IR spectrum -SO ₃ "(1025 cm ^-1 ); β-lactam (1775 cm ^-1 ).

Example 5

(2a, 3a) -1-Sulfomethoxy-2- (aminocarbonyl) -3 - [[(1,1-dimethyläthoxy) carbonyl] amino] -4-oxoazetidin

A) Erythro-3-hydroxy-DL-aspartic acid

Erythro-3-hydroxy-DL-aspartic acid is prepared from trans-epoxysuccinic acid as described by CW Jones ^, et al., Can. J. Chem., Vol. 47 (1969), 4363. Trans-epoxysuccinic acid from fumaric acid as described by GB Payne et al., J. Org. Chem. Vol. 24 (1959), p.

B) β-methyl-erythro-3-hydroxy-DL-aspartate .

A suspension of 5.0 g (33.5 mol) of erythro-3-hydroxy-DL-aspartic acid in 5 0 ml of anhydrous methanol is treated with 6 ml of concentrated hydrochloric acid. The mixture is refluxed for 3 hours, then cooled to room temperature and evaporated under reduced pressure. The residue is taken up in 95% ethanol and the pH is adjusted to 8.0 by addition of pyridine. The resulting white solid is filtered off and dried.

, ._ 30 - '

There are obtained 5.2 g (95% yield) of the desired methyl ester, mp 210 ° C. , '

C) Erythro-3-hydroxy-DL- asparagine

4.0 g (24.1 mmol) of the β-methylaspartate obtained above are dissolved in 40 ml of concentrated ammonia and stirred for about 15 hours at room temperature. Then the reaction mixture is evaporated under reduced pressure and the residual residue dissolved in hot water. The pH is adjusted to 5.0 with 6N HCl, the solution is concentrated under reduced pressure to about 20 ml, and then allowed to stand at 5 ° C. for about 15 hours. The resulting white crystalline mass is separated and dried.

Yield: 3.4 g (95%) of the title compound, mp 233 ° C.

D) Potassium salt of n-tert-butoxycarbonyl-erythro-S-hydroxy-DL-asparagine . f ·

7.0 g (47 mmol) of erythro-3-hydroxy-DL-asparagine are suspended in 50 ml of water and brought into solution by addition of 3N KOH. This solution is adjusted to pH 10.0 and maintained at this pH while dropwise adding a solution of 15.5 g (71 mmol) of di-tert-butyl dicarbonate in 20 ml of tert-butanol. The reaction mixture is stirred for about 15 hours at room temperature and pH 1.0.0. In it, the tert-butanol is distilled off under reduced pressure, the aqueous' residue is adjusted to pH 5.0 with 6N HCl and the solution is concentrated under reduced pressure to a small volume. Then, the ^f · pH with 6N IICL adjusted to 3.0 and the solvent removed under reduced pressure. There are obtained 20 g of a solid containing the desired product in the free acid form and in about quantitative yield together, * with inorganic salts. A 2.9 g portion of this solid is taken up in water and mixed with

- 31 - '

dilute KOH adjusted to pH 6.5. The solution is then chromatographed through 100 ml of HP-20 resin using water and then acetone / water in the ratio 1: 9 as eluent. The desired potassium salt is obtained as residue (1.8 g).

E) v tetrabutylammonium on Aminoxym ethane sulfonic acid

To a solution of 0.635 g (5 mmol) of aminoxymethanesulfonic acid in 2 ml of water is added 1.02 g (3 mmol) of tetrabutylammonium hydrogen sulfate and the pH of the solution is adjusted to 10.0 with dilute KOH. Then the water is distilled off under reduced pressure and the residue is digested with methylene chloride and filtered. The filtrate is dried over sodium sulfate and evaporated. Yield: 1.06 g (2.88 mmol) of the title compound.

F) Potassium salt of Q-sulfomethyl-an-tert-butoxycarbonyl-

erythro-3-hydroxy-DL-asparagine hydroxamate ,

0.792 g (2.77 mmol) of potassium salt of n-tert-butoxycarbonylerythro-3-hydroxy-DL-asparagine are dissolved in 3 ml of water and adjusted to pH 2.4 with dilute H 2 SO 4. Then the solution is concentrated under reduced pressure to a residue, which is evaporated twice from water and then twice from benzene. This residue is dissolved in 4 ml of anhydrous acetonitrile and 8 ml of anhydrous tetrahydrofuran and cooled to 0 ° C. Then, with stirring, 0.424 g (2.77 mmol) of 1-hydroxybenzotriazole monohydrate and then 0.572 g (2.77 mmol) of Ν, Ν'-dicyclohexylcarbodiimide are added to the solution. The mixture is stirred for 2 hours at 0 ⁰ C and-then treated dropwise with 1.06 g (2.88 mmol) of the above prepared Tetrabutylamrnoniumsalzes of Aminoxymethansulfonsäure in 5 ml of acetonitrile

added. After the addition, the reaction mixture is stirred at 0 ^° C. for 4 hours, then filtered and evaporated.

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-32-

reduced pressure to a residue-this is mixed with 10 ml of water and digested at ^{0 0} C until solidification ^. The resulting pellet is filtered off, the aqueous filtrate concentrated to about 3 ml, its pH adjusted to 4.0, and fractionated over 80 ml of Dowex 50 (K) ion exchange resin. The product-containing fractions are collected and concentrated to a small volume. The pH is adjusted to 3.4 and the solution chromatographed on HP-20 resin to give after lyophilization 502 mg (46%) of the title compound as a solid, mp 145 ° C. .

analysis for C 18 ^N 3 ° 9 ^lbs 3K.0, 71H ₂ O: 1 N 29 7 S C H 1 O, 0 4 7 85 15 About: , 42 4 80 O, 45 gef. : , 42 4 , 73 ^: 1O ^H 29 29

G) Tetrabutylammonium s alz of Q-Su lf omethyl-an-tert.-but-

oxycarbonyl-erythro-3-hydroxy-DL-asparagine-hydroxamate 20

To a solution of 104 mg (0.263 mmol) of the above-obtained potassium salt of asparagine hydroxamate in 1 ml of water is added 2.63 ml of 0.1 M tetrabutylammonium hydrogensulfate in 0.5 M KH ₂ PO. buffer solution of pH 5.5. The solu- ² ^ solution is then evaporated to dryness and the residue digested with methylene chloride. Filtration and evaporation of the methylene chloride gives 156 mg (0.26 mmol ·) of the title compound as a residue.

^H ) Potassium salt of ( 2a, 3a) -1-sulfomethoxy -2- (aminocarbonyl) -3 - [[(1,1-dimethylethoxy ) carbonyl] amino] -4-oxoazetidine

140 mg (0.234 mmol) of the above obtained Tetrabutylammoniumsalzös of O-Sulfomethylhydroxamat are dissolved in 1 _f 6 ml of anhydrous methylene chloride and stirred for about 15 hours with 1 g of dry molecular sieve 3A. The solution comes with

Γ - 33 - Π

a syringe and diluted with 0.8 ml of anhydrous methylene chloride. The solution is then added with stirring -50 ⁰ C under argon with 0.12 ml (0.85 mmoles) of triethylamine and then dropwise with 0.08 mL (0.42 iuMol) of trifluoromethanesulfonic anhydride. The reaction mixture is heated to -30 C within 1 hour and then treated with 0.06 ml of triethylamine. After 5 minutes, the reaction mixture is evaporated under reduced pressure and the residue is dissolved in 2 ml of acetone. The solution is cooled to 0 C and treated with a solution of 79 mg of potassium perfluorobutanesulfonate in 1 ml of acetone. Then diethyl ether is added and the solids are removed by centrifugation. Treatment of the pesticides by stirring with 2 ml of Dowex 50 (K) resin in water, filtration and removal of the water under reduced pressure gives the crude potassium salt containing no amines. Chromatography of this crude potassium salt on HP-20 resin using water as the eluent gives 15 mg (20%) of the title compound which, after lyophilization, has the mp 149 ° C.

IR spectrum (KBr): 1786 cm -1 (β-lactam-carbonyl) and 1696 cm (broad, amide and carbamate-carbonyl).

Further examples of compounds prepared according to the invention are:

Monopotassium salt of (3S-trans) - [[(2-amino-4-thiazolyl) -raethoxy-imino) -acetyl] -amino] -4-methyl-2-oxo-1-azetidinyl] oxy] -methanesulfonic acid.

Monopotassium salt of (3S-trans) - [[(2-amino-4-thiazolyl) [(2,2,2-trifluoroethoxy) -imino] -acetyl] -amino] -4-methyl-2-oxo-1-azetidinyl ] oxy] methanesulfonic

Monopotassium salt of (3S-trans) - [[(2-amino-4-thiazolyl) - [(2-amino-2-oxoethoxy) -imino] -acetyl] -amino] -4-trimethyl-2-oxo-1-azetidinyl ] oxy] methanesulfonic

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^Γ - 34 -

ί Dipotassium salt of (3S-trans) - [[(2-amino-4-thiazolyl) - [(carboxy-methoxy) -imino] -acetyl] -amino] -4-ethyl-2-oxo-1-azetidinyl] - oxy] methanesulfonic

Dipotassium salt of (3S-trans) - [[(2-amino-4-thiazolyl) - [[Cl-carboxy-cyclopropyl) -oxy] -imino] -acetyl] -amino] -4-methyl-2-oxo-1 -azetidinyl] oxy] -methansülfonsäure

Monopotassium salt of [3S- [3a (R), 4SS]] - [[3 - [(aminophenylacetyl) amino] -4- ^J methyl-2-oxo-1-azetidinyl] oxy] -methansülfonsäure

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

Monopotassium salt of (3S-tris) - [[3 - [(2-thienylacetyl) amino] -4-methyl-2-OXO-1-azetidinyl] oxy] methanesulfonic acid

Mono potassium salt of (3S-trans) - [[3- [(2, 6-dimethoxyphenyl) acetyl], - amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methane- ^2- sulfonic acid -

Monopotassium salt of [3S- [3a (R), 4β]] - [[3- [[[[(aminocarbonyl) amino] -2-thienylacetylamino] -4-methylthyl-2-oxo-1-azetidinyl ] -

oxy] -methanesulfonic acid ^;

Dipotassium salt of [3S- [3α (R), 4β]] - [[3 - [(carboxyphenylacetyl) amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid

Dipotassium salt of [3S- [3a (-) 4β]] - [[3 - [(phenylsulfoacetyl) amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid

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

L · J

, Monopotassium salt of [3S- [3a (R), 4β]] - [[3- [t [[[2-0x0-3 - [(phenylmethylene) amino] -1-imidazolidinyl] carbonyl] amino ] -phenylacetyl] amino] -4-methyl-2-oxo-1; '- azetidinyl] oxy] methanesulfonic acid

Monopotassium salt of [3S- [3a (Z), 4β]] - [3 - [[2-furanyl- (methoxy-imino) -acetyl] -amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic

Monopotassium salt of [3S (Z)] - [[3 - [[(2-amino-4-thiazolyl) - (methoxy-imino) -acetyl] -amino] -2-oxo-1-azetidinyl] oxy] -methanesulfonic acid

Dipotassium salt of [3S (Z) [- [[3 - [[(2-amino-4-thiazolyl) - [(1-carboxy-1-methylethoxy) -imino] -acetyl] -amino] -2-oxo 1-azetidinyl] oxy] methanesulfonic acid

Monopotassium salt of [3S (Z)] - [[3 - [[(2-amino-4-thiazolyl) - [(2,2,2-trifluoroethoxy) -imino] -acetyl] -amino] -2-oxo-i -azetidinyl] oxy] methanesulfonic

Monopotassium salt of [3S (Z)] - [[3 - [[(2-amino-4-thiazolyl) - [(2-amino-2-oxoethoxy) -imino] -acetyl] -amino] -2-OXO-1 -azetidinyl] oxy] methanesulfonic

Monopotassium salt of [3S- [3a (S), 4β]] - [[3 - [[[(aminocarbonyl) amino] -2-thienylacetyl) amino] -2-oxo-1-azetidinyl] oxy] methanesulfonic acid

Dipotassium salt of [3S- [3a (-), 4β]] - [[3 - [(phenylsulfoacetyl) amino] -2-oxo-1-azetidinyl] oxy] methanesulfonic acid

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

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^Γ - 36 -

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

Monopotassium salt of (3S-cis) - [[(2-amino-4-thiazolyl) - (raethoxy-imino) -acetyl] -amino] -4-methyl-2-oxo-1-azetidinyl] oxy] -methanesulfonic acid " ;

Monopotassium salt of (3S-cis) - [[(2-amino-4-thiazolyl) - [(2,2,2-trifluoroethoxy) -imino] -acetyl] -amino] -4-methyl-2-oxo-1-azetidinyl ] oxy] -methansulfonsaure

- Dipotassium salt of (3S-cis) - [[(2-amino-4-thiazolyl) - [(car- \ boxy-methoxy) -imino] -acetyl] -amino] -4-methyl-2-oxo-1 azetidinyl] oxy] methanesulfonic acid

Dipotassium salt of (3S-cis) - [[3 - [[(2-amino-4-thiazolyl)] - (1-carboxy-1-methylethoxy) -imino] -acetyl] -amino] -2-OXO-4- methyl-1-azetidinyl] oxy] -methansulfonsaure

Dipotassium salt of (3S-cis) - [[(2-amino-4-thiazolyl) - [[(1-carbene)

boxy-cyclopropyl) -oxy] -imino] -acetyl] -amino] -4-methyl-2-oxo-1-azetidinyl] oxy] -methanesulfonic acid

Monopotassium salt of (3S-cis) - [[(2-amino-4-thiazolyl) - [(2

amino-2-oxoäthoxy) imino] acetyl] amino] -4-methyl-2-oxo-lazetidinyl] oxy] -methansulfonsaure

Dipotassium salt of [3S- [3a (R), 4c /.]] - [[3- [(carboxyphenylacetyl) amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid

Monopotassium salt of [3S- [3α (R), 4α]] - [[3 - [[[[[(4-ethyl-2,3-dioxb-1-piperazinyl) carbonyl] amino] phenylacetyl] amino] 4-methyl ^ -2-oxo-1-azetidinyl] oxy] methanesulfonic acid

Γ - 37 ~ ·. Ί

Monokalums of [3S- [3α (S), 4α]] - [[3 - [[[(aminocarbonyl) amino] -2-thienylacetyl] amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic

Monokaliurnsalz of [3S- [3a (R), 4a]] - [[3 - [(Aminophenylacetyl) amino] -4-methyl-2-oxo-1-azetidinyl] oxy] methanesulfonic acid

10

15 20 25 30 35

Claims (15)

'Claim of invention' 1. Process for the preparation of novel β-lactam antibiotics of the general formula I ' ¹ R ₁ -NH-C CR ₃ ρ II 3s / ^D (Il ^ C NOC-SO ₃ H, - ' ίο. , · ·. , · '. '. or their esters and salts, where R _{1 is} an acyl radical, R ₁ is a hydrogen atom or a methoxy group ; 'represents ^,; , , , '·. , j R_ and R _{4 are the} same or different and are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or 4-, 5-, 6- or 7-membered heterocyclic radicals or one of the radicals R and R.sup.1 is a hydrogen atom and the other is an azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethyl, 2-phenylethynyl or carboxyl group or one of the radicals _X, -SX -0-X ^X 3 Ϊ -CH_X, -SX ₅ , -0-X ₂ , ^X 3 Ϊ3 X ₅ X ₅ or -A-C-NX.-X-; D / X _{1 is} an azido, amino, hydroxy, alkanoylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl) sulfonyloxy, phenyl, substituted phenyl or cyano group or a radical of the formula -S-X_ or -O -X ₂ means X 'is an alkyl, substituted alkyl, phenyl, sub- / substituted phenyl, phenylalkyl, (substituted phenyl) alkyl, alkanoyl, substituted alkanoyl, ^Γ - 39 - Represents phenylcarbonyl, (substituted phenyl) carbonyl or heteroarylcarbonyl radical, one of X ₃ and X is hydrogen and the other is hydrogen or alkyl and X ₃ and X ₄ together with the carbon to which they are attached form a cycloalkyl, Xc is formyl, alkanoyl, Phenylcarbonyl, (substituted phenyl) carbonyl, phenylalkylcarbonyl, (substituted phenyl) alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino) carbonyl or cyano group, A represents one of the groups -CH = CH-, -CH ₂ -CH = CH-, - (CH ₂ ) _η τ -CH ₂ ) _n -O-, - (CH ₂ ) J ₁ T ^KH ~ ^or - (CH _{2 represents} J _n , -S-CH ₂ -, η has the value 0, 1, 2 or 3, n ^{1 has} the value 1 or 2, X, - and X- are the same or different and each one D / -. Represent hydrogen atom or an alkyl radical or X, is a hydrogen and X_ is an amino, - substitutiono . I te amino, acylamino or alkoxy group means 20 R ₁ - and R, are the same or different and are hydrogen ίο Ό atoms, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or substituted phenyl radicals or 4-, 5-, 6- or 7-membered heterocyclic radicals, or R ₁ - and R _fi together, with the carbon atom to which they are attached, a cycloalkyl radical or a 4-, 5-, 6 or 7-membered heterocyclic radical or one of R _c and R _{c is} a hydrogen atom and the other is an azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenyläthenyl-, 2-phenyläthinyl or carboxyl group or one of the radicals -CH ₃ X ₁ , - ^S ~ ^X 2 '~ ° ~ ^X 2 ° represents ^the -AC-NX X, characterized in that one 35th ^Γ - 40 - - * ¹ a compound of the formula -NH-CH-c-R ₃ -NH-O-CR ₅ R ₆ -SO ₃ H in which R_, R, R ₁ - and R - have the meanings given above and A represents an amino protecting group, to a product of the formula A ₁ NHt C · ·. λ ^λ Ν-0 cyclized, wherein R ^ is a Wasserstoffätom, the resulting product optionally methoxylated by treatment with a halogenating agent and a methoxylating agent, the amino protecting group splits off and the obtained compound in which R₁ a hydrogen '. ,r · atom, optionally acylated *, 2. Method according to item 1, wherein R "is a hydrogen atom; , '' ' 3 4 Alkyl radical and the other is a hydrogen atom. 3. Method according to item 2, wpbei one of the radicals R and R is not a hydrogen atom. 4, method according to item 2, wherein R ₃ . is a hydrogen atom and R _{4 is} a methyl group. , 5. The method of item 2, wherein R .. is a methyl group and R. is a hydrogen atom. 6. The method of item 2, wherein R ₁ - and R _{fi are} hydrogen atoms. 7. The method of item 2, wherein R ₁ . and R are methyl groups. ' 8. The method of item 2, wherein R is the group (Z) -2-amino-α - [{1-carboxy-1-methylethoxy) -imino] -4-thiazoleacetyl. - 9. The method of item 1, wherein R ", R ₁ . and R _{fi are} each hydrogen atoms and one of R 1 and R 2 10. The method according to item 1, wherein R ~, R- ,, R _c and R _{c are} each hydrogen atoms and R is a methyl group. 11. The method of item 1, wherein R, R, R and R _{fi are} each hydrogen and R _{3 is} a methyl group. 12. The method of item 1, wherein R- is a hydrogen atom. "'r 13. The method of item 1, wherein R- is an amino protecting group. . 14. Method according to item 1, wherein the product [3S- [3a (Z), 4β]] 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[4-methyl-2-oxo Is 1- (sulfomethoxy) -3-azetidinyl] amino] -2-oxoethylidyl] amino] oxy] -2-methylpropionic acid. 15. The method of item 1, wherein the product is [3S- (3a, 4β)] - 1- sulfomethoxy-3-amino-4-methyl-2-oxo-1-azetidine.