CH639664A5 - Process for the preparation of salts of 6-(1-sulphatoethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxyic acid esters - Google Patents

Description

639 664

2nd

PATENT CLAIMS 1. Process for the preparation of salts of 6- (1-sulfato-ethyl) -7-oxo-1-azabicyclo [3.2.0] hept-2-en-2-car-bonic acid esters of the formula

HO3SO

The invention relates to a process for the preparation of new compounds, namely the salts of 6- (l-sulfato-ethyl) -7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid esters.

Derivatives of 6- (l-sulfato-ethyl) -7-oxo-l-azabi-scyclo [3.2.0] hept-2-ene-2-carboxylic acid of the general formula

(I)

CH-,

10th

H03S0

15

s

-N

X- NH.CO.CH.

in which R is an organic radical with up to 16 carbon atoms and X denotes the trans-SO.CH = CH-, the trans-S.CH = CH- or the -S-CH2-CH2 group, characterized in that a salt of a corresponding compound of the formula is esterified.

C02H

(I)

20th

25th

2. The method according to claim 1, characterized in that a disalt of a compound of formula (I) with a compound of formula

R-Q

30th

35

(IV)

40

implemented, in which Q means a group which can be split off.

3. The method according to claim 1, characterized in that reacting a mono salt of a compound of formula (I) with a diazoalkane.

4. The method according to claim 2, characterized in that one uses a compound R-Q, in which Q is a chlorine, bromine or iodine atom or an -O.SO2CH3- or an -O.SOzCaH-tCHî group.

5. The method according to claims 2 or 4, characterized in that one uses a compound R-Q, in which R is the phthalidyl group.

6. The method according to claim 2, characterized in that the compound used is R-Q phthalidyl bromide.

7. The method according to any one of claims 1 to 6, characterized in that one uses a salt of a compound of formula I in which X is the trans-SO-CH = - = CH group.

8. The method according to any one of claims 1 to 6, characterized in that a salt of a compound of formula I is used in which X is the trans-S-CH = CH group.

9. The method according to any one of claims 1 to 6, characterized in that one uses a salt of a compound of formula I in which X is the -S-CH2-CH2 group.

in which X means dietrans-SO.CH = CH-, dietrans-S.CH = CH- or the -S-CH2-CH2 group, and their salts are described in BE-PS 827 331,827 332 and 839 324, in which the aforementioned compounds have been designated as MM 4550, MM 13902 and MM 17880. The two BE-PS 827 331 and 827 332 correspond to the DT-OS 25 13 855 and 24 13 854.

It has now been found that salts of esters of compounds of the general formula (I) are antibacterial substances. In addition, the salts of these esters of compounds of the general formula (I) are also capable of the effectiveness of penicillins and cephalosporins against β-lactamase-producing strains of various Gram-positive and Gram-negative bacteria, such as Staphylococcus aureus, Klebsiella aerogenes, Escherichia coli, Proteus mirabilis and other similar organisms.

The present invention thus relates to the preparation of salts of 6- (l-sulfato-ethyl) -7-oxo-l-azabi-cyclo [3.2.0] hept-2-ene-2-carboxylic acid esters of the general formula (II)

45

HQ3SO

50

IQ

X NH.CO.CH-

co2r

(11)

55

65

in which R is an organic radical with up to 16 carbon atoms and X denotes the trans-SO.CH = CH-, the trans-S.CH = CH- or the -S-CHî-CHî group.

Examples of suitable radicals R are aryl, alkyl, aralkyl and alkenyl radicals which can be substituted by halogen atoms, hydroxyl, nitro, cyano, carboxamido, acetamido, sulfonamido, phenylsulfonyl groups, alkoxy, acyloxy , Aryloxy, aralkoxy, alkylthio, arylthio and / or aralkylthio radicals. Alkyl and alkenyl residues are conveniently straight chain or branched chain residues, but straight chain residues are generally more convenient.

The radical R expediently has up to 12 carbon atoms. Thus R can be the methyl, ethyl, propyl, butyl or benzyl group, the latter being substituted by 1 or 2 halogen atoms, nitro groups and / or alkoxy radicals having 1 to 4 carbon atoms. The Benz

3rd

639 664

Hydrile group, which can be substituted by 1 or 2 halogen atoms, nitro groups and / or alkoxy radicals with 1 to 4 carbon atoms, is also suitable.

Particularly useful esters are those in which the ester group -CO2R has the general formula -CO2R1, which is easily hydrolyzable in the human body, for example in tissues or in the blood, and which provides the parent acid or its salt. This also applies to mammalian tissue in the same way.

Other esters that are particularly suitable are described in the examples.

The radical R1 is expediently one of the radicals listed in the sub-formulas (a) to (c) below:

- CH «

R

(c)

R2

I.

-CH-O-CO-R3

15

(a)

20th

(b)

25th

in which R2 is a hydrogen atom or the methyl group, R3 represents the phenyl or benzyl group or an alkyl or alkoxy radical each having 1 to 4 carbon atoms and R4 represents a hydrogen atom or the methoxy group.

Advantageously, R2 is a hydrogen atom and R3 is the methyl, tert-butyl, phenyl or ethoxy group.

Most suitable is R1 a residue of sub-formula (a) and especially sub-formula (b).

R1 is preferably the phthalidyl groups, since such compounds show a particularly good activity when injected.

Preferred compounds prepared according to the present invention are thus pharmacologically acceptable salts of compounds of the general formula (III)

■ X - NH - CO - CH-

(.IUI

CO - 0

in the X1 the trans-SO.CH = CH-, trans-S-CH = CH- or the -S-CH: -CH2 group is also preferred.

Those compounds in which the radical R has a chiral center can be present as pure optical isomers, for example the R isomer or the S isomer, or as a mixture of the two isomers, for example in the R, S form. Thus, the present invention encompasses both the R- and the S-phthalidyl esters and their mixtures, such as the R, S-phthalidyl esters.

Examples of suitable salts of the compounds of the general formula (II) are the sodium, potassium, calcium, magnesium, ammonium or substituted ammonium salts, for example the trimethylammonium salt, furthermore trimethylamine, 2-hydroxyethylamine, bis (2- hydroxyethyl) amine, tri- (2-hydroxyethyl) amine, benzathine, procaine *, bicyclohexylamine, dibenzylamine, N, N-dibenzyl-ethylenediamine, 1-ephenamine, N-ethyl-piperidine -, N-Benzyl-ß-phenethyl-amine, pyridine, collidine, quinoline or quaternary ammonium salts, such as the tetramethylammonium salt.

The most suitable salts are sodium, potassium or quaternary ammonium salts, for example a tetraalkylammonium salt with 1 to 6 carbon atoms in the alkyl radical, such as the tetra-n-butylammonium and the tetra-n-hexylammonium salt.

The potassium salts and particularly the sodium salts are preferred.

The present invention thus relates to a process for the preparation of salts of the compounds of the general formula (II) by esterifying a salt of a corresponding compound of the general formula (I).

The following processes can be used for esterification:

(a) reacting a disalt of a compound of the general formula (I) with a compound of the general formula (IV)

R-Q (IV)

in which R has the meanings given for the general formula (II) and Q is a radical which can be split off, or

(b) reacting a mono salt of a compound of the general formula (I) with a diazoalkane.

639664

4th

Suitable disalts of compounds of the general formula (I) which can react with compounds of the general formula R-Q include alkali metal salts, such as the sodium or potassium salts, or other customary salts, such as quaternary ammonium salts. 5

Suitable radicals Q are those known atoms or radicals which can be replaced by carboxylate anions in a manner known per se. Such residues include chlorine,

Bromine and iodine atoms, sulfonic acid esters, such as the groups -OSO2CH3 or -OSO2C6H4CH3 and other usual residues, 10 which can be replaced by nucleophilic compounds.

A particularly suitable compound of the general formula (IV) is phthalidyl bromide. Other phthalide derivatives are also advantageous.

This reaction is usually carried out in an aprotic organic solvent, such as dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, acetone, dioxane or acetonitrile, optionally in the presence of a crown ether or similar solvents and at non-extreme temperatures, such as from -5 to + 100 ° C. carried out. It has been found that this reaction can conveniently be carried out in anhydrous dimethylformamide at room temperature. Those compounds in which the radical R has a chiral center are usually initially formed in the R, S form. A separation into the R and S isomers can be achieved by means of conventional methods, such as by chromatography, by inoculation or by crystallization and the like.

The reaction of a mono salt of a compound of the general formula (I) with a diazo compound is a mild process for the preparation of alkyl, aralkyl or substituted alkyl or aralkyl esters. Diazotization can be carried out under customary reaction conditions, for example at not extremely high Temperatures and in a conventional solvent. Such reactions are usually carried out between -5 and + 100 ° C and expediently at room temperature. Suitable solvents for this reaction are lower alcohols, such as methanol and ethanol, and solvents, such as tetrahydrofuran, dioxane and the like. Such solvents usually contain a small amount of water which promotes the solubility of the compounds of general formula (I) in the solvent.

Aqueous ethanol has been shown to be a particularly useful solvent in this reaction. 45

The monoester-monoquaternary ammonium salts of the compounds of the general formula (II) can also be expediently dissolved by dissolving a water-soluble salt of a compound of the general formula (II) in water and then mixing this solution with a solution of a quaternary ammonium halide in one with water immiscible inert organic solvents. The organic solvent is then separated or evaporated to give the quaternary ammonium salt. Suitable organic solvents are halogenated hydrocarbons, such as methylene dichloride or chloroform. The mixing of the two solutions takes place at temperatures between 1 and 100 ° C, for example between Î and 30 ° C. The two solutions are usually mixed together by shaking or stirring 60.

The salts of the compounds of the general formula (II) can be exchanged in a customary manner, for example using an ion exchange resin. Metal ion salts useful for this purpose are

Lithium, sodium and potassium salts.

The salts of the general formula (III) can be obtained in crystalline form, for example by critical

sieren from an inert organic solvent such as ethyl acetate, cyclohexane or mixtures thereof.

Pharmaceutical preparations can be formulated which contain a salt of a compound of the general formula (II), if appropriate together with pharmacologically tolerable carrier materials, diluents, excipients and / or other active compounds.

Medicinal preparations of this type can be in a form which is suitable for oral, topical or parenteral use. For example, the preparations can be used in the form of tablets, capsules, syrups, reconstitutable powders or in a particularly expedient manner in sterile forms for injection or infusion purposes. Medicinal preparations of this type can contain customary pharmacologically acceptable additives, such as diluents, binders, colorants, flavoring agents, preservatives, disintegrants and the like, according to customary pharmaceutical practice, which is known to the person skilled in the art of the formulation of antibiotics, such as penicillins, cephalosporins. Preferred medicinal products are adapted for injection and are, for example, in the form of a sterile solution in water.

The salts of compounds of the general formula (II) can be present in the medicinal preparations as the only active ingredient or together with a β-lactam antibiotic. Suitable β-lactam antibiotics include those which are known to be sensitive to β-lactamases and also those which have substantial resistance to β-lactamases. Such .beta.-lactam antibiotics are ampicillin, amoxycillin, benzylpenicillin, phenoxymethylpenicillin, propicillin, cephaloridine, cefoxitin, cephalothin, cephalexin, carbenicillin, ticarcillin and such in vivo hydrolysed matable-ester compounds such as phenyl, tolyl or indanyl esters of carbenicillin or Ticarcillin or the acetoxymethyl, trimethylacetoxymethyl or phthalidyl esters of ampicillin, benzylpenicillin, amoxycillin, cephaloridine, cephaloglycin and the like. The ratio of salt of a compound of general formula (II) to a β-lactam antibiotic is normally between 20: 1 and 1:20 and in particular between 10: 1 and 1:10, for example between 3: 1 and 1: 3.

The total amount of a compound produced according to the invention, which is present in any individual dosage forms, is usually 50 to 1500 mg and usually 100 to 1000 mg.

Preferred medicinal preparations in single doses can be administered once or several times a day, for example two to four times a day, in the treatment of diseases of the urinary tract, respiratory tract, soft tissue and the like. Thus, the medicinal products can be used in the treatment of such diseases as bronchitis, gonorrhea, otitis media, mastitis and the like.

The examples illustrate the invention.

example 1

0.60 g (1.37 mmol) of the disodium salt of a compound of the general formula (I) in which X is the -S-CH = CH group and which is referred to in the further examples as "compound MM 13902", are treated for 2 hours at room temperature with 0.53 g (4.17 mmol) of methyl iodide in 10 ml of dimethylformamide. After evaporation of the solvent under reduced pressure, the residue is chromatographed on silica gel using a mixture of chloroform and ethanol as the eluent. 0.36 g (= 61% of theory) of the monomethyl ester of the monosodium salt of the compound MM 13902 is obtained as a white solid.

5

639664

UV spectrum: Xmax (H20) = 323 and 228 nm;

IR spectrum: Vmax (KBr) = 1760, 1685, 1620 and 1220-1280 (broad) cm-1.

NMR spectrum: 8

(DMSO-d «) - 1.33 (3H, d, J = 6 Hz, CHa.CH); 1.92 (3H, s, CHs); 2.92 (1H dd, J = 19, J '= 10 Hz, Ha of the ABX system); «3.5 (1H, m, Hb of the ABX system); 3.75 (4H, s + m, CH3O2C and CH.CH.CH); 4.20 (1H, m, Hx of the ABX system); 4.38 (1H, dq, J = 10, J '= 6 Hz, CHjCH.CH); 5.82 (1H, d, J = 14 Hz, CH: CHNH); 7.07 (1H, dd, J = 14, J '= 11 Hz, CH: CHNH); 10.45 (broad) (1H, d, J = 11 Hz, NH.CH :).

The compound can also be prepared as follows: 1.1 g (2.52 mmol) of the disodium salt of the compound MM 13902 are stirred for 2 hours at room temperature with 1.5 g (10.56 mmol) of methyl iodide in 20 ml of N, N-dimethylformamide . After evaporation of the solvent under reduced pressure, the residue obtained is chromatographed on 30 g of silica gel using chloroform with increasing amounts of ethanol up to the ratio chloroform with increasing amounts of ethanol up to the ratio chloroform: ethanol 1: 1. The fractions containing the desired compound are combined and evaporated under reduced pressure. Ethyl acetate is added to the residue and it is evaporated off under reduced pressure. 0.68 g (= 63% of theory) of the monomethyl ester of the mono-sodium salt of the compound MM 13902 is obtained.

Instead of ethyl acetate, other solvents that remove ethanol azeotropically, for example acetonitrile or toluene, can also be used in this step.

Example 2

0.50 g (1.15 mmol) of the disodium salt of the compound MM 13902 are treated for 2 hours at room temperature with 1.00 g (5.85 mmol) of benzyl bromide in 10 ml of dimethylformamide. After working up and chromatography as in Example 1, 0.29 g (= 50% of theory) of the monobenzyl ester of the monosodium salt of the compound MM 13902 is obtained.

UV spectrum: A, max (HîO) = 325 and 226 nm.

IR spectrum: Vmax (KBr) = 1765, 1685, 1620 and 1210 to 1280 (broad) cm1.

Example 3

0.970 g (2.22 mmol) of the disodium salt of the compound MM 13902 are treated for 2.5 hours at room temperature with 1.7 g (6.80 mmol) of p-bromo-benzyl bromide in 17 ml of dimethylformamide. After working up and chromatography as in Example 1, 0.73 g (= 56% of theory) of the mono-p-bromo-benzyl ester of the monosodium salt of the compound MM 13902 is obtained as a white solid.

UV spectrum: Ama * (H2O) = 325 and 226 nm.

IR spectrum: Vmax (KBr) = 1760, 1675, 1620 and 1210 to 1280 (broad) cm-1.

Example 4

1.67 g (3.83 mmol) of the disodium salt of the compound MM 13902 are stirred for 2 hours at room temperature with 2.48 g (11.6 mmol) of p-nitro-benzyl bromide in 30 ml of dimethylformamide. After working up and chromatography as in Example 1, 1.27 g (= 60% of the

Theory) of the p-nitro-benzyl ester of the monosodium salt of the compound MM 13902.

UV spectrum: Xmax (ethanol) = 325.266 (shoulder) and s 220 nm.

IR spectrum: Vmax (KBr) = 1760.1680.1620.1210 to 1280 (broad) cm-1.

10 NMR spectrum: 8 (DMSO-dö) = 1.36 (3H, d, J = 6 Hz, CHsCH); 1.92 (3H, s, CH3CO); 2.96 (1H, dd, J = 19 and 10 Hz, CHa of ABX); 3.52 (1H, dd, J = 19 and 9 Hz CHb from ABX); 3.67 (1H, dd, J = 10.5 and 6 Hz, CH.CH.CH); ~ 4.20 (1H, m, CHx from ABX); 4.42, 5 (1H, dq, J = 10.5 and 6 Hz, CH-CHs); 5.22 and 5.42 (each 1H, d, J = 14 Hz, CG2Ar); 5.80 (1H, d, J = 14 Hz, CH: CH.S); 7.04 (1H, dd, J = 14 and 10.5 Hz, CH: CH.NH); 7.63 and 8.17 (each 2H, d, J = 8 Hz, aromatic protons) and 10.38 (1H, d, J = 10.5 Hz, NH).

20th

Analysis for C2oH2oN3S20ioNa. '/ 2H20:

Ber. (%): C 43.01; H 3.76; N 7.54; S 11.47; Na 4.12 Found (%): C 42.94; H 3.77; N 7.21; S 11.54; Na 4.41.

25th

Example 5

0.30 g (0.69 mmol) of the disodium salt of the compound MM 13902 are treated for 5 hours at room temperature with 0.90 g (3.03 mmol) of p-iodobenzyl bromide in 9 ml of dimethylformamide. After working up and chromatography as in Example 1, 0.15 g (= 34% of theory) of the mono-p-iodobenzyl ester of the monosodium salt of the compound MM 13902 is obtained as a white solid.

35 UV spectrum: Àmax (H2O) = 325 and 232 nm.

IR spectrum: Vmax (KBr) = 1765, 1675, 1620 and 1210 to 1280 (broad) cm-1.

40

Example 6

0.18 g (0.41 mmol) of the disodium salt of the compound MM 13902 are treated for 6 hours at room temperature with 0.55 g (1.85 mmol) of o-iodobenzyl bromide in 5 ml of dimethylformamide 45. After working up and chromatography as in Example 1, 0.07 g (= 26% of theory) of the mono-o-iodobenzyl ester of the monosodium salt of the compound MM 13902 is obtained as a brownish-colored solid.

50 IR spectrum: Vmax (KBr) = 1760,1680,1620 and 1210 to 1280 (broad) cm-1.

55 Example 7

0.25 g (0.57 mmol) of the disodium salt of the compound MM 13902 are treated for 1.5 hours at room temperature with 0.80 g (2.88 mmol) of p-bromophenacyl bromide in 5 ml of dimethylformamide. After working up and chromatographing as in Example 1, 0.21 g (= 60% of theory) of the mono-p-bromophenacyl ester of the monosodium salt of the compound MM 13902 is obtained as a cream-colored solid.

65 UV spectrum: Xmax (ethanol) = 327 and 257 nm.

IR spectrum: vmax (KBr) = 1765, 1690, 1620 and 1210 to 1280 cm-1.

639664

6

Analysis for C2iH2oN2Br09S2Na.H20:

Ber. (%): C 40.06; H 3.50; N4.45; S 10.17; Br 12.72 Found (%): C 39.90; H 3.64; N4.09; S 10.10; Br 12.55.

Example 8

0.30 g (0.69 mmol) of the disodium salt of the compound MM 13902 are treated for 1.5 hours with 0.50 g (2.35 mmol) of bromophthalide in 5 ml of dimethylformamide. After working up and chromatography as in Example 1, 0.08 g (= 21% of theory) of the phthalide ester of the monosodium salt of the compound MM 13902 is obtained as a brownish-colored solid.

UV spectrum: Xmax (H2O) = 333 and 233 nm. 15

10th

IR spectrum: Vmax (KBr): 1275 cm- '.

1775, 1680 (broad), 1620, 1210 and

Chromatograph 40 g silica gel using initially chloroform and then mixtures of chloroform and ethanol to a 3: 2 ratio. Then the fractions containing the ester are combined and evaporated under reduced pressure. The residue is taken up in toluene and the solution is again evaporated under reduced pressure. 260 mg of the monomethyl ester of the monosodium salt of the compound MM 4550 are obtained as a solid.

UV spectrum: A.max = 297 and 245 nm.

IR spectrum: Vmax (KBr) = 1775.1710.1620.1260 cm "1.

The NMR spectrum in deuterated dimethyl sulfoxide shows u. a. Signals at 8 =

1.36 (3H, d, J = 6 Hz); 2.0 (3H, s); 3.77 (3H, s); 6.22 (1H, d, J = 15 Hz); 7.38 (1H, dd, Ji = 15 Hz, J 2 = 10 Hz).

Example 9

0.30 g (0.69 mmol) of the disodium salt of the compound MM 13902 are treated for 2 hours at room temperature with 0.50 g (2.72 mmol) of N-chloromethyl-benzoxazolone in 6 ml of dimethylformamide. After working up and chromatography as in Example 1, 0.155 g (= 40% of theory) of the mono-N-benzoxazolonyl methyl ester of the monosodium salt of the compound MM 13902 is obtained.

UV spectrum: Jimax (H2O) = 330.267 and 225 nm.

20 Example 12

500 mg of the disodium salt of the compound MM 4550 in 5 ml of dimethylformamide are treated with 1.5 g of p-bromo-benzyl-bromide. The mixture is stirred for 3 hours. After working up as in Example 11, 350 mg of 25 of the mono-p-bromo-benzyl ester of the monosodium salt of the compound MM 4550 are obtained.

IR spectrum: Vmax (KBr) = up to 1280 (broad) cm-1.

1775 (broad), 1690, 1620 and 1220

Example 10

0.3 g (0.68 mmol) of the disodium salt of a compound of the general formula (I) in which X is the -S-CH2-CH2 group and which is hereinafter referred to as "compound MM 17880" in 4 ml N, N-dimethylformamide is treated with 0.75 g (3 mmol) of p-bromobenzyl bromide. The mixture is stirred for 2.5 hours. After evaporation of the solvent on a rotary evaporator, the residue is chromatographed on silica gel using mixtures of chloroform and ethanol up to a ratio of 3: 2. After evaporating the fractions containing the ester, adding toluene to the residue and again evaporating the solution, 0.195 g (= 48% of theory) of the mono-p-bromobenzyl ester of the monosodium salt of the compound MM 17880 is obtained.

UV spectrum: A, max (H2O) = 320 nm.

IR spectrum: Vmax (KBr) = 1765.1690.1635.1220 cm "1.

NMR spectrum: 8

(DMSO-ds) = 1.37 (3H, d, 3 = 6 Hz, CHsCH); 1.81 (3H, s, CHsCO); 2.8-3.6 (6H, m, CH2.C.SCH2CH2N); 3.69 (1H, dd, J = 11 and 6 Hz, CH.CH.CH); 4.05-4.6 (2H, m, CH.CH.CH); 5.08 and 5.26 (each 1H, d, J = 14 Hz, CH2Ar); 7.36 and 7.57 (each 2H, d, J = 8.5 Hz, aromatic protons) and 8.10 (1H, broad, NH).

Example 11

816 mg of the disodium salt of a compound of the general formula (I) in which X denotes the -SO.CH = CH group and which is hereinafter referred to as "compound MM 4550" are 0 in 10 ml of N, N-dimethylformamide , 9 ml treated iodomethane. The mixture is stirred for 2 hours. The solvent is then removed on a rotary evaporator and the residue is on

UV spectrum: / W (H2O) = 305.244 (shoulder), 228 nm. IR spectrum: vmax (KBr) = 1780.1710.1620.1260-30 1220 cm "1.

The NMR spectrum in deuterated water shows u. a. Signals at 8

1.43 (3H, d, J = 6 Hz); 2.00 (3H, s); 6.23 (1H, d, J = 15 Hz); 6.96 35 (2H, d, J = 8 Hz); 7.14 (2H, d, J = 8 Hz); 7.32 (1H, d, J = 15 Hz).

Example 13

800 mg of the disodium salt of the compound MM 4550 in 40 8 ml of N, N-dimethylformamide are treated with 1.0 ml of benzyl bromide. The mixture is stirred for 3 hours and then worked up as in Example 11. 420 mg of the monobenzyl ester of the monosodium salt of the compound MM 4550 are obtained.

45

UV spectrum: Xmax (H2O) = 306 and 246 nm.

IR spectrum: Vmax (KBr) = 1780.1705.1620.1220-1260 cm "1.

50

The NMR spectrum in deuterated dimethyl sulfoxide shows u. a. Signals at 8 =

1.36 (3H, d, J-6 Hz, CHaCH); 2.01 (3H, s, C.H3CO); 5.26 (2H, broad singlet, OCH2PI1); 6.24 (1H, d, J = 14 Hz, 55 CH-CH).

Example 14

400 mg of the disodium salt of the compound MM 4550 in 60 4 ml of N, N-dimethylformamide are treated with 1.2 g of p-nitrobenzyl bromide. The mixture is stirred for 2.25 hours and then worked up as in Example 11. 234 mg of the mono-p-nitro-benzyl ester of the monosodium salt of the compound MM 4550 are obtained.

65

UV spectrum: A, max = 250 and 296 (shoulder) nm. IR spectrum: Vmax (KBr) = 1780.1710.1620, 1260-1220 cm "1.

7

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The NMR spectrum in deuterated water shows i.a.

Signals around 5 =

1.53 (3H, d, J = 6 Hz); 2.1 (3H, s); 6.4 (1H, d, J = 15 Hz); 7.33 (IH, d, J-15 Hz); 7.38 (2H, d, J = 8 Hz); 8.03 (2H, d, J = 8 Hz).

Example 15

670 mg of the disodium salt of the compound MM 4550 and 1.58 g of p-methoxybenzylbromide are stirred together in 10 ml of N, N-dimethylformamide for 3 hours. After working up as indicated in Example 11, the mono-p-methoxy-benzyl ester of the monosodium salt of the compound MM 4550 is obtained.

Example 16

50 mg of the disodium salt of the compound MM 4550 and 190 mg of o-iodobenzyl bromide are stirred together in 2 ml of N, N-dimethylformamide for 6 hours. After the solvent has been evaporated off, the residue is triturated with toluene. After centrifugation, 92 mg of residue are collected, which is then chromatographed on cellulose using a 9: 1 mixture of isopropanol and water as the eluent. The desired fractions are combined and evaporated under reduced pressure. The mono-o-iodobenzyl ester of the monosodium salt of the compound MM 4550 is obtained.

IR spectrum: vmax (CHCh) = 1785, 1710,1620,1260-1220 cm-1.

Example 17

185 mg of the disodium salt of the compound MM 4550 in 2 ml of N, N-dimethylformamide are treated with 80 mg of trimethyl-cetoxymethyl bromide in 1 ml of N, N-dimethylformamide. The mixture is stirred for 4.75 hours at room temperature and then left in the refrigerator for 2 days. After evaporation of the solvent, the residue is applied to a short chromatography column with silica gel and eluted with a 3: 2 mixture of ethanol and chloroform. The mono-tri-methylacetoxymethyl ester of the monosodium salt of the compound MM 4550 is obtained from the eluate as a solid.

UV spectrum: X max (H2O) = 296 nm.

IR spectrum: vmax (KBr) = 1780.1705, 1610.1260 cm "1.

Example 18

300 mg of the disodium salt of the compound MM 4550 and 360 mg of N-chloromethyl-benzoxazolone are stirred together in 5 ml of dimethylformamide for 3 hours. After evaporation of the solvent and after working up the mixture as in Example 11, the mono-N-benzoxazolonyl methyl ester of the monosodium salt of the compound MM 4550 is obtained.

UV spectrum: Âmax (H2O) = 306.247 and 226 nm.

IR spectrum: Vmax (KBr) = 1780.1720 to 1710, 1620, 1260 cm "1.

The NMR spectrum in deuterated water (the HOD standard for the measuring device is S = 4.6) shows, among other things. Signals at 8 =

1.40 (3H, d, J = 6 Hz, CH3CH); 2.00 (3H, s, CHaCO); 5.90 (2H, broad singlet, OCH2N); 6.25 (1H, d, J = 14 Hz, CH = CH); 7.0-7.25 (4H, m, ArH); 7.36 (1H, d, J = 14 Hz, CH = CH).

Example 19

60 mg of the disodium salt of the compound MM 13902 are suspended in 5 ml of ethanol. Then water is added until the solution is complete. The solution is cooled to 0 ° C. in an ice bath 5 and then heated together with a solution of 90 mg p-toluenesulfonic acid in 6 ml ethanol cooled to 0 ° C. The resulting solution is stirred for about 5 seconds and then treated with an ethereal solution containing excess diazomethane. After 20 minutes at 10 room temperature, the solvents are evaporated off under reduced pressure. The semi-solid residue is triturated with ether, filtered and washed with ether. The residue is chromatographed on silica gel, using a mixture of butanol, ethanol and ls water in a ratio of 16: 4: 7 as the eluent. The monomethyl ester of the monosodium salt is obtained as an amorphous solid.

Example 20

2 # 500 mg of the disodium salt of the compound MM 4550 are dissolved in water. The solution is passed through a column of an ion exchange resin "DOWEX 50W-X8" which has been converted into the calcium form by treatment with an aqueous slurry of calcium carbonate 25. After evaporating the fractions containing the desired compound under reduced pressure, this is obtained Calcium salt of the compound MM 4550.

IR spectrum: vmax (KBr) = 1755.1690.1620.1260-1220 cm "1.

30th

The calcium salt obtained in this way is taken up in 9 ml of N, N-dimethylformamide and mixed with 1.4 g of p-bromobenzyl bromide. The mixture is stirred for 3 hours, then the solvent is evaporated. The residue 35 is chromatographed on silica gel using a mixture of chloroform and ethanol as the eluent. 180 mg of the mono-p-bromo-benzyl ester of the calcium salt of the compound MM 4550 are obtained.

Example 21

191 mg of the mono-p-bromo-benzyl ester of the monosodium 45 salt of the compound MM 13902 in 6 ml of water are shaken with a solution of 138 mg (0.95 equivalents) of tetrahexylammonium bromide in 10 ml of methylene chloride. The organic layer is separated, filtered through cotton wool and evaporated. The desired compound is obtained in the form of a foam in practically quantitative yield.

IR spectrum: Vmax (CH2CI2) =

3200-3400 (broad), 1775 (β-lactam-C = 0), 1695 (broad, ester and amide carbonyl groups), 1620 (C = C) cm-1.

55

The NMR spectrum in deuterochloroform shows i.a. Signals at 8 =

6.20 (1H, d, J = 14 Hz, -S-CH = CH-NH); 7.55 (5H, m, -S-CH = CH-NH and aromatic protons); 10.06 (1H, d, 60 J = 10 Hz, SCH = CHNH).

Example 22

0.05 g of the monomethyl ester of the monosodium salt of the compound MM 13902 are dissolved in water. The solution is stirred vigorously with a solution of 0.04 g of tetrabutylammonium hydrogen sulfate in 5 ml of methylene dichloride. After 5 minutes the organic layer is separated and dried over anhydrous magnesium sulfate. After this

40 IR spectrum: Vmax (CHCl3 / (CH3) 2NCHO) = 1790.1720, 1620, 1260 cm "1.

639664

8th

Evaporation of the solvent gives 0.61 g of crude tetrabutylammonium salt of the compound of general formula (II) in which R of the group (C4Ho) 4N and the rest R1 are the methyl group. Rapid chromatography on silica using a mixture of chloroform and ethanol as the eluent gives a pure sample of the monomethyl ester of the monotetrabutylammonium salt of the compound MM 13902 in a yield of 0.04 g

IR spectrum: Vmax (CHCb) =

1775 (ß-lactam-C = 0), 1695 (unsaturated ester and

Enamide-C = 0), 1625 and 1200-1280 (broad) (sulfate) cm-1.

Example 23

0.05 g of the mono-p-nitro-benzyl ester of the monosodium salt of the compound MM 13902 are treated with tetrabutylammonium bisulfate as described in Example 22. 0.05 g of the mono-p-nitro-benzyl ester of the mono-tetrabutyl ammonium salt of the compound MM 13902 is obtained as a rubber-like compound.

IR spectrum: Vmax (CHCb) =

1775 (β-lactam-C = 0), 1690 (unsaturated ester and

Enamide-C = 0), 1625 and 1200-1280 (broad) (sulfate) cm-1.

Example 24

0.22 g of the mono-p-iodo-benzyl ester of the monosodium salt of the compound MM 13902 are dissolved in 2 ml of water. The solution is treated with 0.100 g of an aqueous solution of S-benzyl-isothiuronium chloride at 5 ° C. A white precipitate forms immediately. Chloroform is added and the product extracted into the organic phase, which is dried over anhydrous magnesium sulfate and then evaporated. 0.15 g of the mono-p-iodo-benzyl ester of the S-benzyl-isothiuronium salt of the compound MM 13902 is obtained.

IR spectrum: Vmax (CHCb) = 1780,1690,1670 and 1625 cm-1.

Example 25

0.055 g of the mono-p-bromophenacyl ester of the monosodium salt of the compound MM 13902 are treated with 0.04 g of S-benzyl-isothiuronium chloride in the same manner as in Example 24. 0.047 g of the mono-p-bromophenacyl ester of the S-benzylisothiuronium salt of the compound MM 13902 is obtained as a rubbery substance.

IR spectrum: Vmax (CHCb) = 1780, 1695, 1670 and 1625 cm-1.

Example 26

0.11 g of the mono-p-nitro-benzyl ester of the monosodium salt of the compound MM 13902 are treated as in Example 24 with 0.075 g of S-benzyl-isothiuronium chloride. 0.080 g of the mono-p-nitro-benzyl ester of the S-benzylisothiuronium salt of the compound MM 13902 is obtained as a rubbery substance.

IR spectrum: Vmax (CHCb) = 1775.1690 (broad) and 1620 cm-1.

Example 27

The monobenzyl ester of the monosodium salt of the compound MM 4550 is dissolved in water. A chloroform solution of methyl trioctyl ammonium chloride is added to the solution. The mixture is shaken thoroughly. After the phases have been separated, the chloroform layer is evaporated. The monobenzyl ester of the monomethyl-trioctyl-ammonium salt of the compound MM 4550 is obtained.

IR spectrum: Vmax (CH2CI2) = 1785.1720.1620.1240-1220 cm-1.

Antibacterial and synergistic activity of the mono-trimethylacetoxymethyl ester of the monosodium salt of the compound MM 4550 (el) and of the mono-phthalide ester of the monosodium salt of the compound MM 13902 (e2)

The aforementioned two esters (el) and (e2) are examined in parallel experiments with the compounds MM 13902 and MM 4550 against 5 β-lactamase-producing organisms both alone and in combination with ampicillin against 3 of these organisms. The results obtained are shown in Tables I and II.

Table I

Antibacterial effect of (el) and (e2) as a minimum inhibitory concentration in µg / ml

β-lactamase

Compound staphylo-

coccus Klebsiella Proteus aureus aerogenes mirabilis E. coli E. coli

Russell E70 C889 JT39 JT10

Disodium salt

MM 4550

12.5

6.25

25th

12.5

25th

Disodium salt

MM 13902

0.2

0.8

0.2

0.8

0.4

(el)

125

125

125

8.0

250

(e2)

31

15.6

15.6

31

62

Tables

Synergistic effect of (el) and (e2) with ampicillin and cephaloridine as minimum inhibitory concentration in (ig / ml

connection

Concentra

Staphylo-

Proteus

Klebsiella

tion of the coccus mirabilis aerogenes

Connection aureus

C889

E70

in ng / ml

Russell

Ampicillin

_

250

> 2000

1000

(el)

1.0

250

> 500

> 500

10th

4th

15.6

500

(e2)

1.0

4th

15.6

> 500

5

<0.5

1.0

250

In vivo activity of the mono-phthalide ester of the monosodium salt of the compound MM 13902 (e2) and the mono-phthalide ester of the monosodium salt of the compound MM 4550 (e3).

The two aforementioned esters (e2) and (e3) are investigated in parallel experiments with the compounds MM 13902 and MM 4550 by administration by means of subcutaneous injection (in aqueous phosphate buffer solution with a pH of 6.6). In this study, 4 doses 1, 2, 3 and 4 hours after an intraperitoneal infection with Escherichia coli 8 are injected.

The following results are obtained:

investigated connection CDo

MM 4550 (disodium salt) 3.9 mg / kg x 4

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

9

639664

(e3) 22.0 mg / kg x 4

MM 13902 (disodium salt) 10.5 mg / kg x 4

(e2) 4.4 mg / kg x 4

In a similar test against Staphylococcus aureus Smith, the following results are obtained:

investigated connection CDo

MM 13902 (disodium salt) 23.5 mg / kg x 4

(e2) 7.8 mg / kg x 4

Example 28

1.05 g of the disodium salt of the compound MM 4550 and 625 mg of bromophthalide are stirred for 2 hours at room temperature together with 19 ml of N, N-dimethylformamide. The solvent is then evaporated off on a rotary evaporator and the residue is chromatographed on 50 g of silica gel using a mixture of chloroform and ethanol in a ratio of 1: 1 as the eluent. The fractions containing the ester are combined and evaporated on a rotary evaporator. Then toluene is added to the residue and the solution is again evaporated on a rotary evaporator. The mono-phthalide ester of the monosodium salt of the compound MM 4550 is obtained as a solid.

UV spectrum: Àmax (H2O) = 306 and 230 to 235 nm.

IR spectrum: Vmax (KBr) = 1785, 1720-1700 (broad), 1620, 1260 and 980 cm-1.

The NMR spectrum shows, among other things, in deuterated dimethyl sulfoxide. Signals at 8 =

1.33 (3H, d, J ~ 6 Hz); 1.98 (s) and 2.01 (s) (3H, COCH3 of the two epimers); 6.20 (d, J = 14 Hz) and 6.26 (d, J = 14 Hz) (1H, S-CH = C, of the two epimers).

Example 29

200 mg of the disodium salt of the compound MM 4550 in 2 ml of water are shaken with 350 mg (2 equivalents) of cetyl-benzyl-dimethylammonium chloride in 2 ml of dichloromethane. The dichloromethane layer is dried over anhydrous magnesium sulfate and evaporated. 397 mg of the diquartary ammonium salt of the compound MM 4550 are obtained as a rubbery substance.

IR spectrum: Vmax (CH2Ch) = 1765,1690,1620 cm-1.

33 mg of methyl chloroformate in 5 ml of dichloromethane are cooled to −30 ° C. and the diquaternary ammonium salt of the compound MM 4550 in 8 ml of dichloromethane which contains 1 drop of dimethylbenzylamine is added dropwise. After the addition has ended, the mixture is stirred at -30 ° C. to -10 ° C. for 45 minutes until the IR spectrum indicates that the mixed anhydride has formed [vmax (CH2CI2) = 1820.1790, 1620 cm-1] . At the temperature of -30 ° C, 1 ml of ethanol is added and the mixture is stirred for 15 minutes at -10 ° C, then about 10 minutes at 0 ° C, then 45 minutes at 10 ° C and finally 60 minutes at room temperature.

The mixture is then evaporated under reduced pressure and the residue is taken up in a mixture of water (pH 7.0) and ethanol. The solution is run through an "Amberlite 120" exchange resin in the sodium ion form. After evaporation of the eluate, the residue is chromatographed on 10 g of silica gel and eluted with a mixture of chloroform and ethanol in

3: 2 ratio. The monoethyl ester of the monosodium salt of the compound MM 4550 is obtained.

The NMR spectrum shows in deuterated water (the HOD standard of the measuring device is 8 = 4.6) and others. Signals at 8 =

1.26 (3H, t, J = 8 Hz, CH3CH2); 1.44 (3H, d, J = 6 Hz, CH3CH); 2.04 (3H, s, CH3CO); 6.34 (1H, d, J = 14 Hz, CH = CH); 7.62 (1H, d, J = 14 Hz, CH = CH).

Instead of the ion exchange process, the conversion of the monoester of the monoquaternary ammonium salt into the monoester of the monosodium salt of this compound can also be prepared by shaking a dichloromethane solution of the ester with water which contains a sodium salt such as sodium tetrafluoroborate or sodium iodide. After separation of the layers and evaporation of the aqueous layers, the monoester of the monosodium salt of the compound MM 4550 is obtained. This process works, provided that the quaternary ammonium iodide or the tetrafluoroborate is relatively insoluble in water.

Example 30

30 mg of the monomethyl ester of the monosodium salt of the compound MM 4550 in 2 ml of water are treated with 3 ml of chloroform which contains 27 mg of cetyl-benzyl-dimethyl-ammonium chloride. After shaking, the chloroform layer is separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The mono-methyl ester of the mono-cetyl-benzyl-dimethyl-ammonium salt of the compound MM 4550 is obtained in about 80 percent yield.

IR spectrum: Vmax (CHCb) = 1785, 1705 (broad), 1620 cm-1.

Example 31

105 mg of the disodium salt of the compound MM 4550 in 2 ml of water are treated with 184 mg of cetyl-benzyl-dimethyl-ammonium chloride in 2 ml of dichloromethane. After shaking, the dichloromethane layer is separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The di (cetyl-benzyl-dimethyl-ammonium) salt of the compound MM 4550 is obtained.

IR spectrum: Vmax = 1775.1695.1625 cm-1.

The diquartary ammonium salt of the compound MM 4550 is dissolved in 2 ml dichloromethane and mixed with 0.5 ml methyl iodide. After the mixture has been stirred for about 2 hours, the solvent and the excess methyl iodide are removed under reduced pressure. The residue is chromatographed on 10 g of silica gel using a mixture of chloroform and ethanol with increasing ethanol content to a chloroform to ethanol ratio of 3: 2. About 30 percent yield, based on the starting compound MM 4550, is obtained from the monomethyl ester of the mono-cetyl-benzyl-dimethyl-ammonium salt of the compound MM 4550.

The esterification of the di (cetyl-benzyl-dimethyl-ammonium) salt of the compound MM 4550 in a solution of anhydrous 1,2-dimethoxyethane can also be carried out. After concentration to a small volume, cetyl-benzyl-dimethyl-ammonium iodide crystallizes out, and the monomethyl ester of the mono-cetyl-benzyl-dimethyl-ammonium salt of the compound MM 4550 is obtained from the mother liquors.

One can confirm the structure of this ester

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

639 664

10th

obtained by converting the ester to the monosodium salt using the following two methods:

(a) 1 equivalent of sodium iodide is added to a concentrated solution of the monomethyl ester of the mono-cetyl-benzyl-dimethyl-ammonium salt of the compound MM 4550 in 1,2-dimethyloxyethane. After the cetyl-benzyl-dimethyl-ammonium iodide has crystallized out, the sodium salt is obtained from the mother liquors. Chromatographic purification gives the monomethyl ester of the monosodium salt of the compound MM 4550, which is identical to that of Example 11.

(b) A solution of the monomethyl ester of the mono-cetyl-benzyl-dimethyl-ammonium salt of the compound MM 4550 in dichloromethane is shaken with water which contains 1 equivalent of sodium tetrafluoroborate. After the aqueous layer has been separated off and evaporated, followed by chromatography of the residue on silica gel, the monomethyl ester of the monosodium salt of the compound MM 4550 is obtained.

Example 32

100 mg of the mono-p-nitro-benzyl ester of the monosodium salt of the compound MM 4550 and 70 mg of cetyl-benzyl-dimethyl-ammonium chloride are dissolved in 5 ml of water and 5 ml of chloroform. After shaking, the mixture is allowed to separate into layers and the chloroform layer is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The mono-p-nitro-benzyl ester of the mono-cetyl-benzyl-dimethyl-ammonium salt of the compound MM 4550 is obtained in about 80 percent yield.

IR spectrum: Vmax (CHCb) = 1785, 1710 (broad), 1620 cm-1.

Example 33

52 mg of the monomethyl ester of the monosodium salt of the compound MM 4550 and 44 mg of benzyl triphenylphosphonium chloride are shaken together in 5 ml of water and 5 ml of dichloromethane. After the dichloromethane layer has been separated off, it is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. 76 mg of the monomethyl ester of the monobenzyl triphenylphosphonium salt of the compound MM 4550 are obtained as a semi-solid foam.

IR spectrum: Vmax (CH2CI2) = 1790.1710 (broad), 1610 cm-1.

Example 34

492 mg of the disodium salt of the compound MM 17880 in 5 ml of dimethylformamide are treated with 1.0 g of p-nitro-benzyl bromide. The mixture is stirred for 90 minutes. After working up as in Example 1, 200 mg of the mono-p-nitro-benzyl ester of the monosodium salt of the compound MM 17880 are obtained.

Example 35

0.2 g (0.46 mmol) of the disodium salt of the compound MM 13902 are treated for 3 hours at room temperature with 0.25 g (1.47 mmol) of methyl tosylate in 5 ml of dimethylformamide. After working up and chromatography as in Example 1, 0.06 g (= 30% of theory) of the monomethyl ester of the monosodium salt of the compound MM 13902 is obtained as a white solid.

Example 36

3 drops of a 15-crown 5-ether and 0.35 g (2.05 mmol) of benzyl bromide are added to a suspension of 0.3 g (0.69 mmol) of the disodium salt of the compound MM 13902 in 10 ml of acetonitrile. After stirring for 3 hours at room temperature, the mixture is worked up as indicated in Example 1. 0.145 g (= 42% of theory) of the monobenzyl ester of the monosodium salt of the compound MM 13902 is obtained as an almost white solid.

Example 37

1 g of a sample of the crude, approximately 60 percent pure disodium salt of the compound MM 17880 is treated with 1 ml of methyl iodide in 15 ml of dimethylformamide. After 2 hours the solvent is evaporated under reduced pressure and the residue is chromatographed on 30 g of silica gel using chloroform with increasing amounts of ethanol to a ratio of chloroform: ethanol of 2: 3 as eluent. The fractions containing the desired product are combined and evaporated under reduced pressure. Ethyl acetate is added to the residue and the solution is again evaporated under reduced pressure. 0.25 g of the monomethyl ester of the monosodium salt of the compound MM 17880 is obtained as a light yellow solid.

UV spectrum: Ä.max (H2O) = 314 nm.

IR spectrum: Vmax (KBr) = 1765,1700,1660 (broad) and 1220-1270 (broad) cm-1.

NMR spectrum: 5

(DMSO-ds) = 1.35 (3H, d, J = 6 Hz, CHsCH); 1.80 (3H, s, CHaCO); 2.8-3.8 (7H, m, CH • CH • CH • CH2, C • SCH2CH2N); 3.65 (3H, s, CO2CH3); 3.95-4.6 (2H, m, CH • CH • CH) and 8.0 (1H, broad, NH).

Example 38

0.05 g (0.086 mmol) of the mono-p-bromo-benzyl ester of the monosodium salt of the compound MM 13902 are dissolved in 5 ml of water. The solution obtained is shaken with a solution of 0.032 g (0.08 mmol) of cetyl-benzyl-dimethyl-ammonium chloride in 5 ml of dichloromethane. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. 0.074 g (= 93% of theory) of the mono-p-bromo-benzyl ester of the mono-cetyl-benzyl-dimethyl-ammonium salt of the compound MM 13902 is obtained as a foam.

IR spectrum: Vmax (CH2CI2) = 1780, 1700.1685 (shoulder) and 1625 cm-1.

Example 39

A solution of 0.10 g (0.23 mmol) of the monomethyl ester of the monosodium salt of the compound MM 13902 in 5 ml of water is mixed with a solution of 0.09 g (0.23 mmol) of cetyl-benzyl-dimethylammonium chloride in 5 ml of dichloromethane treated in Example 40. 0.156 g (= 87% of theory) of the monomethyl ester of the mono-cetyl-benzyl-dimethyl-ammonium salt of the compound MM 13902 is obtained as a rubber-like substance.

IR spectrum: Vmax (CHCb) = 1780, 1695 and 1630 cm-1.

Example 40

1.0 g (2.29 mmol) of the disodium salt of the compound MM 13902 is treated for 1.5 hours at room temperature with 0.60 g (2.82 mmol) of bromophthalide in 15 ml of dimethylformamide. After evaporation of the solvent under s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

11

639 664

The residue is chromatographed under reduced pressure on 30 g of silica gel using chloroform with increasing amounts of ethanol to a ratio of chloroform: ethanol of 1: 1 as the eluent.

The few initial fractions that contain the monophthalide ester of the compound MM 13902, as shown by thin-layer chromatography, slowly secrete white crystals. These are nitrided. Yield: 0.03 g. The mother liquors and the other fractions are combined and evaporated under reduced pressure. Ethyl acetate was added to the residue and the solution was again evaporated under reduced pressure. 0.62 g (= 50% of theory) of the monophthalide ester of the monosodium salt of the compound MM 13902 is obtained as a cream-colored amorphous solid. u

UV spectrum: Ln ^ HiO) = 333 and 233 nm.

IR spectrum: vmax (KBr) = 1775.1680 (broad), 1620, 1210 and 1275 cm-1.

The white crystals also contain the desired monophthalide ester of the compound MM 13902.

NMR spectrum: ô

(DMSO-d &) = 1.32 (3H, d, J = 6Hz, CHhCH); 1.92 (3H, s, CHjCO); 2.98 (1H, dd, J = 20 and 10 Hz, Ha from ABX); 3.45-3.75 (2H, m, Hb of ABX and CHCHCH); 4.05-4.55 (2H, m, CHCHCH); 5.80 (1H, d, J -14 Hz, CH = CH • S); 7.05 (1H, dd, J = 14 and 11 Hz, NH • CH = CH); 7.49 (1H, s, CChCHO); 7.55-8.0 (4H, m, aromatic protons).

When using the I5o determination method described in BE-PS 827 926, the sodium salts of the esters, produced according to the present invention, show the following iso values:

Ester of compound MM 13902

Ester Enterobacter Ps. Proteus adhesive. E. coli JT 4 ps. Aeruginosa staph. aureus cloacae P99 aeruginosa A mirabilis C 889 aerogenes E 70 Dalgleish Russell

Benzyi

0.022

> 2.5

0.009

4.0

> 0.5

0.312

0.563

Benzoxazolonylmethyl

0.04

1.8

<0.008

1.0

0.03

<0.008

0.24

p-NCh-benzyl

0.016

19.2

0.022

0.09

1.9

0.198

2.2

methyl

0.002

0.16

0.006

> 40

> 40

0.37

23

p-Br benzyl

0.014

31

0.012

0.4

0.4

0.049

0.2

p-J benzyl

0.003 *

0.8

0.01

0.8

0.4

0.06

0.22

o-J-benzyl

0.0002 *

0.06

0.002

0.025

0.03

0.06

0.2

p-Br-phenacyl

0.008 *

0.02

0.02

0.02

0.02

0.02

1.6

Phthalide

<0.004

0.015

0.06

0.235

0.5

0.18

0.68

* Obtained using ß-lactamase from Citrobacter freundii Mantio, which is either the same enzyme as from Enterobacter cloacae or a very similar enzyme of the I A class.

Ester of compound MM 17880

Ester Enterobacter Ps. Proteus adhesive. E. coli JT 4 ps. Aeruginosa staph. aureus cloacae P 99 aeruginosa A mirabilis C 889 aerogenes E 70 Dalgleish Russell

Methyl 0.116 0.6 0.004-19.5 2.32

p-Br-Brombenzyi 0.022> 40 0.007 0.6 0.4 0.057 1.4

Ester of the compound MM 4550

Ester Enterobacter Ps. Proteus adhesive. E. coli JT 4 ps. Aeruginosa staph. aureus cloacae P 99 aeruginosa A mirabilis C 889 aerogenes E 70 Dalgleish Russell

Benzoxazolonylmethyl <0.008 trimethylacetoxymethyl 0.015

Methyl> 40

Benzyl> 40

1.84 0.02> 4

> 4 0.4> 1

> 40 0.01 1.2

> 40 0.002 1.9

0 <0.008 0.82

> 1 0.85

0.35 0.14 23.0

0.38 0.14 2.8

B