CS203097B2 - Process for preparing derivatives of d-6/alpha-substitude ureidogroup/-p-hydroxybenzylcarboamido/penicilanic acid - Google Patents

Description

The present invention relates to a process for the preparation of D-6- {α- [substituted ureido] -p-hydroxybenzylcarboxamidoipenicillanic acid derivatives.

Some semi-synthetic penicillins, such as ampicillin, amoxycillin, sulbenicillin, carbenicillin, dicloxacillin and nafcillin, have been developed and sold on a large scale over the last two decades. Although these semi-synthetic penicillins have been found to be effective in treating a large number of infectious diseases caused by various microorganisms, there remains a need for additional antibiotics effective against some specific microorganisms, such as Pseudomonas and Proteus sp. It is an object of the present invention to provide novel amoxycillin derivatives, 6 - [? - amino- (p-hydroxybenzylcarboxamido) penicillanic cyeelines, having an interesting action against microorganisms such as Pseudomonas and / or Proteus sp.

A process for the preparation of D-6- {a- (substituted ureido) -p-hydroxybenzylcarboxamide ipenicillanic acid derivatives of the general formula I

HO77 o

CH ~ C

NH i

Y

-nh-ch-ch 'i

N

-CH

AND

COOE (U where

E represents a hydrogen atom, a cation forming a pharmaceutically acceptable salt or a pharmaceutically acceptable ester moiety of formula II

-CH 2 —O — CO — R or —CH ₂ —S — CO — R (Π), where

R represents a straight or branched (C 1 -C 4) alkyl radical, optionally substituted by an alkoxy or alkylthio (C 1 -C 4) alkyl radical, and

Y is a group of formula III

Z2 —C — NH — P (III),

O O Zl where

Z 1 and Z 2 are the same or different and are C 1 -C 4 alkoxy, C 1 -C 4 alkyl optionally substituted by halogen, hydroxyl, and OM, where M is a pharmaceutically acceptable salt cation, and salt hydrates, is characterized by: by reacting a compound of formula IV

i z

Y (IV) wherein

Q represents a hydrogen atom or a silicon or phosphorus atom bearing substituents such as C1-C4 alkyl, phenyl, benzyl, C1-C4 alkoxy (preferably a trialkylsilyl group, for example trimethylsilyl group) and Y 'has the same meaning as Y or represents a group which, after reaction, can readily be converted to the group given in definition Y (which may be attacked or affected under the reaction conditions) with 6-aminopenicillanic acid or a derivative of the general formula V hLN-CH ² I-c-

C ₍ H

-Ni ^ rH

-CH

I / COOE (V) where

E 'represents a salt-forming moiety, a protecting group that can be easily removed after the reaction and does not interfere with the reaction, or a pharmaceutically acceptable ester-enhancing ester, in the presence of carbodiimide (e.g. dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide optionally mixed with 1-hydroxybenzotriazole and 1-cyclohexyl-3- (2- (N-methylmorpholino) ethyl] carbodiimide) as a condensing agent, and then deprotecting the compound obtained and optionally converting the acid to a pharmaceutically acceptable salt or an ester.

The salt-forming cations in the definition of E and M are those which form non-toxic, pharmaceutically acceptable salts of the compounds of formula I, such as sodium, potassium, ammonium or calcium salts or amine salts, e.g., tri (lower) alkylamine, procaine or benzylamine. Hydrates of the salts of the compounds of formula I are included in the invention.

Examples of groups of formula III are di (lower) alkoxyphosphinylaminocarbonyl, diphenoxyphosphinylaminocarbonyl, diphenylphosphinylaminocarbonyl, di (lower) alkylphosphinylaminocarbonyl, hydroxybenzylphosphinylaminocarbonyl, hydroxy (lower) alkoxyphosphinylaminocarbonyl, hydroxyphenylphosphinylaminocarbonyl, hydroxyphenylphosphinylaminocarbonyl, hydroxyphenylphosphinylaminocarbonyl laminocarbonyl, lower] alkoxy-benzyloxy-phosphininylaminocarbonyl, phenyl-benzyloxy-phosphinylaminocarbonyl, lower alkylbenzyloxyphosphinylaminocarbonyl, dibenzyloxyphosphinylaminocarbonyl, dihydroxyphosphinylaminocarbonyl, aminocarbonyl, alkoxycarbonyl, aminocarbonyl, aminocarbonyl, aminocarbonyl, lower-1-carboxylic acid .

Examples of an easily removable protecting group represented by E 'in Formula V are optionally substituted benzyl (e.g. p-nitrobenzyl, p-methoxybenzyl), benzhydryl, phenacyl (e.g. p-halo substituted phenacyl), 2,2,2-trichloroethyl, trityl, t -butyl, isobutyl, isobornyl, or a silicon or phosphorus atom bearing a lower alkyl, halo-substituted lower alkyl, aryl, aralkyl, lower alkoxy, halo-substituted alkoxy, lower alkylthio group, aralkoxy, di (lower jalkylaminoalkyl and lower alkoxy and lower alkoxy) alkylenedioxy and halogen atoms.

The desired D- (- j-2-amino-2- (p-hydroxyphenyl) acetic acid starting material for the preparation of the starting acid of formula IV or activated derivatives thereof is known, for example, from German Laid-Open No. 2355785.

Compounds of formula IV are novel compounds and as such are within the scope of the invention. Reactions of compounds of formula VI can be prepared

Q - O - ey - ^ CH - C - OE '(VII where

Q and E ‘are as defined above with the compound of formula VII

Zi ‘/

O = C = N — P1 \

O Z2 ‘[VII], where

ZT and Zz 'are the same or different and are C 1 -C 4 alkoxy, C 1 -C 4 alkyl optionally substituted by halogen, phenoxy, benzyl or benzyloxy optionally substituted by C 1 -C 4 alkyl, nitro- or a (C 1 -C 4) alkoxy group, in an inert organic solvent at a temperature in the range of -30 to + 30 ° C, preferably -5 to + 5 ° C, and preferably under anhydrous conditions and then optionally removing the protecting group E 'and any other protecting groups. Advantageously, the obtained acid of formula IV can be converted directly in situ into a compound of formula I by adding a suitable reactant to the obtained reaction solution as mentioned above.

The starting compounds of formula VIIIa can be prepared according to known methods, as described, for example, by G. I. Darkatsch, Angew. Chem. 81, No. 11, 407-436 (1969), L.I. Samarai et al., Zh. Obahch. Khim. 39, 1'51.1 (1969 J, G. 1. Deikatsch et al., Zh. Obshch. Khim, 38, No. 8, pp. 1784-1888 (1968), ES Gubnitskaya et al., Zh. Obshch. Khim 49, 1205-1210 (1970), LI Samarai et al., Zh Obshch, Khim 39, No. 8, 1712-1725 (1969), AV Narbut et al., Zh Obshch. Khim, 38, no. 6, pp. 1321-1324 (1968) and G. Tomaschewski et al., Arch Pharm. 301, p. 520, (1988).

A typical compound of the invention is

D-6- {of- [3- (benzyloxy / ethyl / phosphinyl) ureido] -β-hydroxybenzylcarboxamidojpenicillanic acid, [3- [tazyloxy- / ethoxy / phosphinyl] ureido] -β-hydroxybenzylcarboxamido } penicillanic acid,

D-6- (α- [3- (hydroxy / ethyl / phosphinyl) ureido] -β-hydroxybenzylcarboxamidojpenicillanic acid,

D-6- (α- [3- (hydroxy / benzyloxy / phosphinyl) ureido] -β-hydroxybenzylcarboxamide) -penicillanic acid,

D-6-η- [3- (hydroxy / ethoxy / phosphinyl) ureido] -β-hydroxybenzylcarboxamide iodicillanic acid,

D-6- (α- [3- (dibenzyloxyphosphinyl) ureido] -p-hydroxybenzylcarboxamido} penicillanic acid,

D-6 - {N- [3- (benzyloxy- / methoxy / phosphinyl) ureido] -β-hydroxybenzylcarboxamido} D-6- {a- [3- (hydroxy / methoxy / phosphinyl) ureido] -p (hydroxybenzylcarboxamido) psnicilic acid a

D-6- (α- [3- (dihydroxyphosphinyl) ureido] -β-hydroxybenzylcarboxamido} penicillanic acid,

D-6- (α- [3- (benzyloxy / methyl / phosphinyl) ureido] -p-hydroxybenzylcarboxamido] penicillanic acid,

D-6- [3- [benzyloxy / i-propyl / phosphinyl] ureido-p-hydroxybenzylcarboxamido} penicillanic acid,

D-6- (α- [3- (benzyloxy / tert-butyl / phosphininyl) ureido] -β-hydroxybenzylcarboxamidojpenicillanic acid,

D-6-} a- [3- (benzyloxy / tert-butoxy / phosphinyl) ureido] -p-hydroxybenzylcarboxamido] penicillanic acid,

D-6- (α- [3- (Hydroxy / methyl / phosphinyl) ureido] -p-hydroxybenzylcarboxamido} penic acid,

D-6- (α- [3- (hydroxy / iso -propyl / phosphinyl) ureido) -β-hydroxybenzylcarboxamidojpenicillanic acid,

D-6- (α- [3- (hydroxy / tert-butoxy / phosphinyl) ureido] -p-hydroxybenzylcarboxamidojpenicillanic acid,

D-6- (α- [3- (hydroxy / tert-butyl / phosphinyl) ureido] -β-hydroxybenzylcarboxamido} penicillanic acid,

D-6- (of- [3- (benzyloxy / phenoxy / phosphinyl) ureido-1-p-hydroxybenzylcarboxamido] penicenoic acid,

D-6-β- [3- (benzyloxy / isopropoxy / phosphinyl) ureido] - β -hydroxybenzylcarboxamide ienicicanoic acid,

D-6 - {N- [3- (hydroxy / phenoxy / phosphinyl) ureido] -β-hydroxy-benzylcarboxamidojpenicillanic acid,

D-6- {α- [3- (diphenoxy / phosphininyl) ureido] - p -hydroxybenzylcarboxamidojpenicillanic acid,

D-6- (α- [3- (diethoxyphosphinyl) ureido] -β-hydroxybenzylcarboxamido-pentenoic acid,

D-6-β- [3- (hydroxy / iso-propoxy / phosphinyl) ureido] -β-hydroxybenzylcarboxamide ipenicillanic acid, and their sodium, potassium and mono-salts (mono-, di- and trivalent salts) and pharmaceutically acceptable esters, the ester group corresponds to formula III; Preferred are compounds of formula I wherein Z 1 and / or Z 2 represents a hydroxyl group or an -OM group. In particular, compounds in which Z 1 represents a hydroxyl group or an -OM group and Z 2 represents a methoxy or ethoxy group having an interesting antimicrobial effect. As usual, the D-modification of these compounds exhibits the most interesting antimicrobial effects.

The compounds of the formula I are preferably used for therapeutic purposes in the form of a non-toxic salt, such as sodium, potassium, ammonium or calcium salt. Other salts can be used, including nontoxic, suitably crystalline salts with organic bases, such as amines such as trialkylamines, procaine and dibenzylamine.

For the treatment of bacterial infections, the antibacterial compounds of the invention may be administered topically, orally and parenterally, according to conventional methods of antibiotic administration. They are administered in unit doses containing an effective amount of the active ingredient in combination with a suitable physiologically acceptable carrier.

Single doses may be in the form of liquid preparations, such as solutions, suspensions, dispersions or emulsions, or in solid form, such as powders, tablets and capsules.

The invention also relates to pharmaceutical compositions comprising an effective amount of at least one compound of formula I in admixture with a suitable physiologically acceptable carrier. These pharmaceutical compositions may also include one or more therapeutic ingredients in addition to a compound of the invention. The term "effective amount" as used in conjunction with the disclosed compounds means an amount sufficient to destroy or inhibit the growth of susceptible microorganisms in conventional administration, in other words, an amount sufficient to control the growth of bacteria. An effective amount can be readily determined by a standard method used to determine the relative effect of antibacterial agents when used against susceptible organisms at various possible routes of administration.

Suitable carriers can be any conventional physiologically acceptable substances that can serve to facilitate the administration of the therapeutically active compound. The carriers may have an auxiliary function, such as a diluent, a flavor, flavor, binder, delaying agent or stabilizer. Examples of carriers include water, which may contain gelatin, acacia, alginate, dextran, polyvinylpyrrolidone or sodium carboxymethylcellulose, aqueous ethanol, syrup, isotonic saline, isotonic glucose, starch, lactose or any other such commonly used in the pharmaceutical industry of human and veterinary use .

Further disclosed is a method of inhibiting bacterial growth by administering an effective amount of the disclosed antibacterial compounds to host bacteria. For example, the method can be used to treat bacterial infections and in animals by administering an effective amount of an antibacterial compound of the invention to a host.

The novel penicillanic acid derivatives of the formula I can also be used as growth accelerators in ruminants.

they are also useful in in vitro applications, as solutions for disinfection purposes at a concentration of 0.1 to 1 wt. % dissolved or suspended in a suitable inert carrier for use by washing or spraying.

Some typical compounds of the invention were tested for in vitro antibiotic activity by serial agar dilution tests as follows:

A stock solution of antibiotic 2,000 µg is prepared in a sterile suitable vehicle. Dilute twice with sterile 1/20 mol phosphate buffer pH 6.5 (KH 2 PO 4 - NaOH). Place 1 ml of each diluted solution in 19 ml of liquor and heart agar in a sterile Petri dish. The solidified surface is inoculated with test organisms and incubated for 24 hours at 37 ° C. The minimum inhibitory concentration (MIC), i.e. the lowest concentration of antibiotic that completely inhibits the growth of the test organism, is expressed in mg / ml.

In some cases, the MIC values were determined according to the micro-dilution test performed as follows:

drops of the test antibiotic stock solution at a known concentration are dispensed into a first 9-hole test plate using a sterile Pasteur pipette. After flushing the pipette three times with physiological saline, two drops of the test organism's stock solution in the nutrient medium are placed in all openings except for opening 8. In the first opening, dilute the test compound solution in half; then, after mixing the liquid in the first opening and adding 2 drops of this mixture to the second opening and so on up to the opening 8, dilution of the test compound solution is obtained by geometric series. The aperture 9 contains no antibiotic and serves to control the growth of the test organism in a blank. The test plate is incubated at 30 ° C or 37 ° C for 18 hours.

The antibacterial activity test, the results of which are shown in the following tables, is carried out with groups of 6 female Sviss SPF mice weighing 20 g.

Blood and urine samples are collected following intraperitoneal and oral administration of the test compound at a dose of 100 mg / kg in physiological saline.

The content of the administered antimicrobial compound in these samples was determined qualitatively according to Vincent's test procedure by measuring the diameter of the inhibition zones around a 7 mm diameter paper disc that was impregnated with the sample and placed on nutrient agar broth in a Petri dish where the desired microorganism was cultured. Mean values of two or three independent tests are indicated.

For quantitative determination of the test compound content in blood samples, the diameters of the inhibition zones around the sample paper impregnated paper rolls and the serum standard sample solutions of the compound are measured and the unknown content is determined in a standard manner.

The protection tests, the results of which are shown in the following tables, were performed on groups of 10 female Sviss SPF mice.

Mice from each group are infected intraperitoneally with the selected microorganism. The antimicrobial compound solution is administered as intended and 5 times daily. Treatment lasted 1 day and the test animals were observed for 7 days. The ED 50 -values and the ratio of activity relative to the indicated comparative compounds were determined according to conclusive analysis.

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AntLbacterial effect Apl. ABA MIC ratio of effect in the sword (mouse). merge y / ml infection cf. administration of MIC

Urinary Inhibition Zones 100 mg / kg i.p. i. p. o. oral. χ / ml taken at 2.5 hr.

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Example 1

Preparation of D- (-) - N - (3- (diethoxyphosphinyl) urea) -4-hydroxy-phenylacetic acid ml (120 mmol) of N, O-bis-trimethylsilyl acetamide was added to a suspension of 10.0 g (60%). mmol) of D- (-) - N-parahydroxyphenylglycine in 150 ml of methylene chloride After stirring at room temperature for 45 minutes and refluxing for 30 minutes, a precipitate is still present, after addition of an additional 14.4 ml (60 mmol) of N, O- the bis-trimethylsilyl acetamide was refluxed for 2 hours.

To the reaction mixture was added 16.8 g (60 mmol) of freshly distilled diethylphosphoryl isocyanatidate dissolved in 60 ml of dichloromethane at room temperature. After stirring for 15 minutes, the reaction mixture was poured into water and the pH adjusted to 1.5, then extracted with a 1: 1 mixture of butanol and ethyl acetate. After drying over anhydrous magnesium sulfate, the combined extracts were filtered and concentrated in vacuo, a solid precipitated which was purified by crystallization from 500 ml of ethanol and 200 ml of water (yield 26.7%).

The structure of the prepared compound was confirmed by magnetic resonance spectrum and infrared spectrum:

Magnetic Resonance Spectrum (in CDCl3-dimethylsulfoxide-d6-DCOOD, 60 Mc, tetramethylsilane (TMS) as reference, δ in ppm):

1.30 (t, 6H);

4.13 (multiplet, 4H);

5.23 (s, 1 H),

6.80 (d, 2H).

7.21 (d, 2H).

Infrared spectrum (KBr):

3500—2800, 3300, 1705, 1640, 1540, 1520

1450, 1280, 1240, 1220, 1050, 980, 770 cm Example 2

Preparation of D- (-) -? - [3- (diphenoxyphosphinyl) ureido] -4-hydroxyphenylacetic acid

15.8 ml (66 mmol) of N, O-bis-trimethylsilyl acetamide are added to a suspension of 5.51 g (33 mmol) of D- (-) -. Alpha.-parahydroxyphenylglycine in 25 ml of methylene chloride. After stirring at room temperature for 45 minutes and refluxing for 30 minutes, a precipitate was still present. An additional 7.9 ml (33 mmol) of N, O-bis-trimethylsilyl acetamide was added and refluxed for 2 hours.

9.24 g (33 mmol) of diphenylphosphoryl isocyanatidate dissolved in 33 ml of methylene chloride are added at room temperature. After stirring for 15 minutes, the reaction mixture was poured into water and adjusted to pH 7, then extracted with ethyl acetate.

The pH is then adjusted to 2 and then extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the ethyl acetate extracts were filtered and concentrated to precipitate a solid which was purified by crystallization from acetone-benzene.

Yield 9.22 g (63.6%).

The structure of the prepared compound was confirmed by magnetic resonance spectrum and infrared spectrum:

3400—2400, 3350, 3150, 3050, 2850, 1710,

1640, 1595, 1540, 1520, 1490, 1450, 1360, 1275, 1235, 1210, 1185, 1160, 1070, 1030, 1016,

990, 960, 760, 740 cm -1.

Magnetic resonance spectrum (in CDCl3-dimethylsulfoxide-d6-1: 1, 60 Mc, tetramethylsilane (TMS) as reference, <S in ppm):

5.17 (d, 1H),

5.6 (very broad s, 4H),

6.77 (d, 2H).

7.0-7.5 (multiplet, 12H).

Example 3

Preparation of D- (-) -? - {3- [benzyloxy (ethoxy) phosphinyl) ureido] -4-hydroxy-phenylacetic acid ml (120 mmol) of N, O-bis-trimethylsilyl acetamide was added to a suspension of 10.0 (60 mmol) of D- (-) -. Alpha.-parahydroxyphenylglycine in 150 ml of methylene chloride. After stirring at room temperature for 45 minutes and refluxing for 30 minutes, a precipitate was still present. After addition of an additional 14.4 ml (60 mmol) of N, O-bis-trimethylsilyl acetamide, the mixture was refluxed for 2 hours.

To the reaction mixture, 60 mmol of benzyl (ethyl) phosphoisocyanatidate dissolved in 60 ml of dichloromethane was added at room temperature. After stirring for 15 minutes, the reaction mixture was poured into water and the pH adjusted to 3, then extracted with ethyl acetate.

After drying over anhydrous magnesium sulfate, the combined extracts are filtered and concentrated in vacuo, the residue is stirred in diethyl ether and the precipitate formed is filtered off. Yield 34.2 g.

After recrystallization twice from aqueous ethanol, the yield was 31%.

The structure of the prepared compound was confirmed by magnetic resonance spectrum and infrared spectrum.

Magnetic Resonance Spectrum (in dimethylsulfoxide-de-DCOOD, 60 Mc, TMS as comparator, δ in ppm):

1.26 (t. 3H);

4.10 (multiplet, 2Hj,

5.06 (Cl, 2H),

5.13 (s, 1 H),

6.81 (d, 2H).

7.26 (d, 2Ή) a

7.40 (s, 5H).

Infrared spectrum (KBr):

3600-2700, 3300, 1720, 16 ⁷ 0, 1640, 1540,

1510 1445 1270 1210 1180 1020 910

740, 700 cm ¹ .

Example 4

Preparation of D - (-) -? - {3 - [[ethoxy] (hydroxy) phosphinyl] -ureido-4-hydroxyphenylacetic acid disodium salt

To a mixture of 10 g (23 mmol) of D- (-) -? - {3- [benzyloxy (ethoxy) phosphinyl] ureido-4-hydroxyphenylacetic acid (prepared according to Example 3), 4 g of sodium bicarbonate, 1.5 g 10% palladium on carbon catalyst, 100 ml 96% ethanol and 100 ml water are hydrogen. An additional 0.5 g of catalyst was added per hour, and after 1.5 hours another 1 g of catalyst was added.

Reduction was carried out for 1 hour, the reaction mixture was filtered through celite (R) hyflosupercel, and the filtrate was concentrated in vacuo. The residue was dissolved in methanol and the desired compound was precipitated with ether. Yield 8.0 g (90%) of pale pink. The structure of the prepared compound was confirmed by magnetic resonance spectrum and infrared spectrum:

Magnetic Resonance Spectrum (TMS as comparator, <$ in ppm, in dimethylsulfoxide-ds (DCOOD, 60 Mc)

1.1 (t, 3 H),

3.8 (multiplet, 2 H),

5.08 (s, 1H),

6.72 (d, 2H).

7.16 (d, 2 H).

Infrared spectrum (KBr):

3600—2800, 1660, 1600, 1540, 1520, 1395, 1260, 1090, 1060, 955, 880, 780 cm @ ¹ .

Example 5

Preparation of D-6- {α- [3- (diphenoxyphosphinyl) ureido] -p-hydroxybenzylcarboxamide

-N ^ S ( ^{CH 2} )

CH 2 Cl 2 / ml of dichloromethane was added to a suspension of 2.65 g (6.0 mmol) of α- [3- (diphenoxyphosphines)] ureido-4-hydroxyphenylacetic acid and 1.40 g (7.3 mol) of 1- ethyl 3 (3-dimethylamino-propyl) carbodiimide hydrochloride in 25 ml of tetrahydrofuran. After stirring for 7 minutes, 1.45 g (6.6 mmol) of 6-aminopenicillanic acid, which was previously silylated with 0.97 ml (6.6 mmol of triethylamine (TEA) and 0.84 ml (6.6 mmol)), was added. TEA and 0.84 mL (6.6 mmol) of trimethylchlorosilane TMCS in 15 mL of dichloromethane.

After 2 hours, thin layer conversion was 40% (R ₍ = 0.7, 1: 5: 4 acetic acid: ethyl acetate)) to give a yellow oil which was collected and removed. the mixture was poured into water at pH 7 and extracted with ethyl acetate.

The pH was adjusted to 4.7 and extracted with ethyl acetate. After drying over magnesium sulfate, filtration, evaporation of ethyl acetate and addition of 2 mmol of sodium hexanoate, the desired product, whose structure could be confirmed by magnetic resonance spectra, is isolated in a yield of 1.23 g (32%). According to thin layer chromatography, the product obtained is almost pure. The compound obtained is probably a D-L mixture.

The starting N - [3-diphenoxyphosphinyl / ureido] -4-hydroxyphenylacetic acid has a melting point of 160-170 ° C (with decomposition).

Infrared spectrum:

990, 1200, 1650 and 1710 cm ^-1, NMR (DMSO-U6) 60 Mc, TMS, 5 hodnotv ppm

5.15 (d, C H),

6.6—7.4 (aromatic Hj.

Example 6

Preparation of sodium D-6- (α- [3- (benzyloxy) ethoxy (phosphinyl) ureido] -p-hydroxybenzylcarboxamido-iodoicenoate ml of dichloromethane is added to a suspension of 1.0 mmol of [3- (benzyloxy) ethoxy (phosphinyl) ureido] -4-hydroxyphenylacetic acid and 0.25 g (1.2 mmol) of 1-ethyl-3- (3-dimethylamino-propyl) carbodiimide hydrochloride in 4 ml of tetrahydrofuran After stirring for 7 minutes, 0.25 g (1.1 mmol) of 6-aminopenicillanic acid, which was previously silylated with 0.16 ml (1.1 mmol) of TEA and 0.14 ml (1.1 mmol) of TMCS in 2.5 ml of dichloromethane.

After 2 hours the TLC (Rf ₌ 0.7 in acetic acid (ethyl acetate) acetone 1: 5: 4) was about 50%. The reaction mixture was poured into water of pH = 7, after separation of the oily precipitate, and extracted with ethyl acetate.

The pH was adjusted to 4.7 and extracted with ethyl acetate. After drying over magnesium sulfate, filtration, partial evaporation of ethyl acetate and addition of sodium hexanolate, the desired product, whose structure was confirmed by magnetic resonance spectrum, is isolated in 46.6% yield and is almost pure by thin layer chromatography.

The starting α- [3- (benzyloxy-ethoxy) -phosphinyl] -ureido] -4-hydroxy-phenylacetic acid has mp 122-127 ° C (dec.).

Infrared spectrum:

1020, 1220, 1670 and 1720 tin ¹ , magnetic resonance spectrum (d 6 -dimethylsulfoxide, 60 Mc, TMS, δ-values in ppm):

1.2 (t, _CH3);

4.1 (m, -C-CH 2 O 3),

5.1 (m, C 8 H 5 CH 2 O),

7.0 and 7.4 (aromatic HJ.

In the same way, N- [3- (benzyloxy) ethoxy (phosphinyl) ureido] -4-hydroxyphenylacetic acid and [3- (diethoxyphosphinyl) ureido] -4-hydroxyphenyl-

acetic, which has t. 166-169 ° C (dec. Infrared spectrum: 1040, 1220, 1640 and 1705 cm’i and magnetic resonance spectrum (d 6 -dimetbyl sulfoxide, 60 Mc, TMS, δ-values in ppm): 1.3 (m, CH ₃ ), 4.1 (m, CH 2), 5.15 [d, CH], 7.0 (q, arom. Example 7 In the same way as in previous Examples 5 and 6 are prepare compounds wherein Z1 and Z2 have the following meanings: Zi Zz phenoxy benzyloxy methyl benzyloxy tert-butyl benzyloxy isopropyl benzyloxy isopropoxy benzyloxy phenoxy hydroxy methyl hydroxy tert-butyl hydroxy isopropyl hydroxy isopropoxy hydroxy Example 8 Capsules are prepared in a conventional manner and contain, as an active ingredient, a penicillin derivative prepared according to any of the following: 5 and 6. The composition of the capsule is as follows:

active compound 500 mg and 250 mg magnesium stearate 5—25 mg 2—15 mg lactose sufficient sufficient amount amount for 1 capsule for 1 capsule

capsules may be used for oral administration. Example 9

Tablets containing the active ingredient penicillin prepared according to any of Examples 5 and 6 are prepared in a conventional manner.

The active compound polyvinylpyrrolidone corn starch magnesium stearate lactose

500—750 mg

15—25 mg

100-200 mg 5-10 mg sufficient for 1 tablet (about 100-200 mg) tablets can be used for oral administration.

Example 10

From a penicillin derivative prepared according to one of Examples 5 and 6, a dry powder for an injection mixture is prepared in a conventional manner.

g and 5 g of sterile sodium salt of the active compound admixed with a conventional excipient are introduced aseptically into a vial suitable for injection under a nitrogen atmosphere. The vial is closed with a rubber stopper that is fastened with an aluminum ring to eliminate gas exchange or micro-organism penetration.

Typical excipients may be glucose (usually in an amount suitable to obtain a final isotonic solution) buffers, stabilizers (e.g. Na 2 EDTA), preservatives, wetting agents and antifoams.

Before use, the powder is dissolved in a suitable amount of sterile pyrogen-free water.

Example 11

From penicillin derivatives prepared according to either of Examples 5 and 6, a syrup is prepared by mixing the following ingredients:

Active Ingredient sodium carboxymethylcellulose sodium saccharinate methyl p-hydroxybenzoate aroma dye sucrose water added to volume

Syrups can be used her.

10-15 mg

100-500 mg 0.10-1 g 0.1 g

100—500 mg

25-10 mg 50 g 100 ml for oral administration

Claims (1)

A process for the preparation of D-6- {t - [substituted ureido] β-hydroxybenzylcarboxamido-iodoicillanic acid derivatives of the formula I NH AND Y kde E represents a hydrogen atom, a cation forming a pharmaceutically acceptable salt or a pharmaceutically acceptable ester moiety of formula II -CH ₂ —O — CO-R or -CH 2 -S-CO-R (II) wherein R represents a straight or branched (C 1 -C 4) alkyl radical, an optionally substituted (C 1 -C 4) alkoxy or alkylthio group in the alkyl radical, and Y is a group of formula III Z ₂ From —C — NH — P (III), II II \ o O Zi where Z 1 and Z 2 are the same or different and are C 1 -C 4 alkoxy, C (CH 2 _from q — N — CH COOE (i) a C 1 -C 4 alkyl group optionally substituted by a halogen hydroxyl group and an OM group wherein M represents a cation forming a pharmaceutically acceptable salt and salt hydrates characterized in that a compound of formula IV is reacted CH-COOH NH y '(IV) wherein Q represents a hydrogen atom or a silicon or phosphorus atom bearing substituents such as C 1 -C 4 alkyl, phenyl, benzyl, C 1-4 alkoxy, preferably a trialkylsilyl group, for example a trimethylsilyl group, and Y 'has the same meaning as Y or is a group that can be readily converted to a group as defined in Y after reaction, which can be attacked or affected under the reaction conditions, with 6-aminopenicillanic acid or a derivative of formula V hLN-CH' ² I o = c ~ -SX ^C , ^H 7h -N — CH I / COOE E 'represents a salt-forming moiety, a protecting group that can be easily removed after the reaction and does not interfere with the reaction, or a pharmaceutically acceptable ester-enhancing ester, in the presence of a carbodiimide such as dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide optionally mixed with 1-hydroxybenzoltriazoles and 1-cyclohexyl-3- {2- [2- (N-methylmorpholino) ethyl] carbodimide as a condensation agent, and then deprotecting the compound obtained and optionally converting the acid to a pharmaceutically acceptable salt thereof. a suitable salt or ester as defined above.