DD263773A1 - PROCESS FOR THE PREPARATION OF NEW ALLOPHANOYL-AMINOBENZYLPENICILLINE - Google Patents

Abstract

The invention relates to a process for the preparation of novel allophanoyl-aminobenzylpenicillins of the general formula I in which R1, R2H, halogen, lower straight-chain or branched alkyl or alkoxy, cyano, nitro, amino or SO3H group R3, R4H, lower or branched alkyl groups APhenylrest partially or fully hydrogenated, optionally substituted R5 represent a physiologically acceptable cation or an easily cleavable ester group under physiological conditions. These compounds have high antibiotic activity, in particular against so-called problem germs and are suitable as therapeutics and as active ingredients for pharmaceutical preparations. Formula (I)

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of novel allophanoyl-amino-benzylpenicillins of the general formula I in which R ", R ² HH, halogen, lower straight-chain or branched alkyl or alkoxy, alkylthio, alkylsulfonyl, carboxy, cyano , Nitro-.Aminp orSO ₃ H groups

R ³ , R ⁴ = H, lower straight-chain or branched alkyl groups A = phenyl radical, partially or fully hydrogenated, optionally substituted

R ⁵ = represent a physiologically acceptable cation or an easily cleavable ester group under physiological conditions.

These compounds have high antibiotic activity, in particular against so-called problem germs, and are therapeutics and suitable as active ingredients for pharmaceutical preparations.

Characteristic of the known technical, η solutions

A large number of semisynthetic penicillins have already been described, which differ in their substituents on the amino group of 6-aminopenicillanic acid and, as a result, also in their physico-chemical behavior, but above all in the range of action and intensity. It is known that derivatives of 6-aminopenicillanic acid, which carry a phenylacetic acid radical as a substituent on the amino group, which additionally has a strongly polar group on the 2-carbon atom of the sidechain, although a lower activity against gram-positive bacteria, but now good Possess activity against gram-negative bacteria. The best known and most widely used therapeutic agent in this group of semisynthetic penicillins is ampicillin, whose acyl side chain is derived from D (-) - α-amino-phenylacetic acid. However, the semisynthetic penicillins belonging to this group of compounds also have gaps in the spectrum of activity, i. H. There are pathogenic germs that are not sensitive to these drugs. Since their combat is problematic, they are also called problem germs

 Important representatives of these Problomkeime are:

Pseudomonas aeruginosa

Proteus mirabilis

Klebsiella pneumoniae

Serratia marcescens, Salmonella

It is also known that by further Oerivatisierung the primary amino group of Aminobenzylpenicillins (ampicillin), the effectiveness against certain germs, which include the problem germs, amplified, reduced, but also aufgohobei. can be. Numerous compounds have been described which have arisen formally by acylation of this amino group of ampicillin, some of which even, due to their effectiveness, have found special germs in therapy.

In the group of semisynthetic penicillins related to the invention, acylcarbamoyl derivatives (NL 6901646, 6908909, US 3,479,339,348,192,3433188, DE 1959920), derivatives of unsubstituted, have been known. Allophanic acid (DE 3483188) and those in which the terminal nitrogen atom is an alkyl radical (DE 3483 IfO), unsubst. Aryl radical (DE 2,447,626), acyl radical (DE 2226822,2152967,2152968) or those which are substituted in which both N atoms (i.e., in the 2 and 4 positions) are substituted, i. in addition to the o.g. Substituents also on the N in 2-F'jS'tion a ge .'-.-. '□, unsaturated straight-chain, cyclic, optionally halogenated alkyl radical (DE 2152967,2152% <3,22689> \ 3E 767648), or in which both nitrogen atoms are part of a heterocycle (DE 2104579,210458G, OS AlJ? t)%. DD 117882). As might be expected, these compounds differ in their effect profile and intensity as a function of the L.>> χΙίΚ.

Object of the invention

The aim of the invention is the development? new semisynthetic penicillins, o ^; As a result, germane germs are active and, in particular, can be used against so-called problem germs

Explanation of the essence of the invention

The invention has for its object to develop Verfanren, with the help no .e substituted Allophanoylaminobenzylpenicilline can be prepared technically simple and under favorable economic conditions ι.

According to the invention, the object can be achieved by correspondingly substituted allophanic acids (derivatives) of the general formula II in which B is an activated form of the carboxyl group and the remaining substituents are the above-mentioned.

Own meaning, after

Embodiment A:

entedor directly with about molar amounts of a Aminobenzylpenicillins whose 3-carboxyl group is blocked, in the presence of a proton acceptor, at temperatures between 0 and 20 ° C, preferably 5 to 15 ⁰ C, in an inert anhydrous or

water-soluble solvent or mixed solution is reacted or after ,

Embodiment U:

in the first stage, under conditions A comparable conditions, with an amino acid of formula III, preferably to the D (-) form, whose carboxyl group is temporarily blocked and the reaction product is reacted with 6-APS

In both embodiments, the acid chlorides can be used with advantage as an activated form of allophanic acid, since they are generally substituted by bocannon, starting from a suitable primary amine and phosgene, via the stage of the isocyanate and the diol, by reaction with another suitable substituted Amine resulting substituted urea, by re-reaction with phosgene are well accessible (US-PS 3337621, NI.-PS 1910S60, DE-OS 2115096).

However, the acidicides, mixed anhydrides or other activated forms and methods customary in peptide chemistry can also be used with almost the same result.

This may be necessary in all cases where the production of the acid chloride encounters difficulties.

The temporary blocking of the carboxyl group of the respective amino acids to be aclated, for example aminobenzylpenicillin, which is necessary both in the case of embodiment A and B, can be achieved by conversion into esters which are readily cleavable again later (for example trimethylsilyl, benzyl), but more simply salt formation. Which cation is chosen depends on the solvent system in which you want to work. When working under anhydrous or near anhydrous conditions, a tertiary ammonium salt is advantageously chosen, for. As the triethylammonium salt, which allows working under homogeneous conditions due to the solubility. When working in strong water-containing solvents or solvent mixtures but also alkali metal salts can be used with equal success.

For separation of starting material and isolation of the desired end products, the different solubility in organic media under weakly acidic conditions can be exploited. For this purpose, an extract of Allophanoylaminobenzylpenicilline is washed in a water-immiscible or limited miscible solvent with acidified water. The isolation of the free acids of the allophanoyiaminobenzylpenicillins can be achieved by distilling off the solvent by precipitation by adding the concentrated, purified extracts with good stirring into a suitable second solvent having poor penicillin dissolution properties, or by careful acidification of the aqueous salt solutions crystallize the new penicillins if necessary.

The conversion of the free acid into a desired water-soluble salt form was carried out in the usual way by neutralization of an aqueous suspension with a mild alkali or by precipitation from an organic extract with the solution of a suitable cation donor.

The progress of the acylation reaction and the quality of the final and intermediate products can be monitored easily and quickly with the aid of thin-layer chromatography.

To demonstrate the desired structure of the final products obtained according to the formula I, the following analytical methods can be used

- IP Sprek'ruskopie

- Nuclear resonance spectroscopy

- Elemental analysis

- asymmetric and iodometric titration

- in selected cases mass spectroscopy

The compounds summarized in Table 1 were prepared in this manner (see Table 1).

In order to demonstrate the antibacterial activity of the newly synthesized compounds, a standardized test procedure was used, which includes testing the activity against Gram-negative pathogens (Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella pneumoniae, Serratia marcescens, Salmonella gallinarum) and β-lactamase stability. In the series of newly synthesized compounds, activities were found in the area of Gram-negative problematic germs that far exceed the range of action and intensity of action of ampicillin, in some cases comparable to and even beyond mezlocillin. Increasing efficacy has been achieved mainly against Pseudomonas, Proteus, Klebsiella and Serratia strains.

There is also a significant technical advance compared to bekannton allophanoyl-arninobenzylpenicillinen,

d. H. those compounds in which the terminal N atom of the additional side chain carries an unsubstituted aryl radical (verb.25) or an alkyl radical (verb 26 = (2,4-dimethylallo-panoyl) -ampicilli (i)) ß-Lactamasestabilität be recorded (see Table 2).

The compounds 1,5 and 23 show a significant increase in activity against Pseudomonas aeruginosa compared to ampicillin and also carbenicillin. Against Proteus vulgaris, such an increase in activity has been achieved in compounds 24, 6.4, 23, 3, 14 and 18.

Above the ampicillin and far above the carbenicillin activities against Klebsiella pneumoniae are observed in the compounds 24,14 and 18. In compounds 6, 4, 3 and 23 they even reach the point of view of highly effective mezlocillin.

Against Serratia marcescens, compounds 25 and 3 have activities corresponding to carbenicillin and mezlocillin which are considerably higher than those of ampicillin and azlocillin.

With respect to Salmonella gallinarum, compounds 6,4,3,1 and 23 show increasing activities up to the range of effectiveness of mezlocillin. A higher β-lactamase stability than ampicillin, azlocillin and mezlocillin have the following compounds: 3> 13> 19> 18> 14> 12> 5> 2> 1 = 23> 21> 22> 24 ampicillin.

The greatest progress has been achieved with compound 23. It is more effective than carbenicillin in its efficacy against Pseudomonas and pioteus and better than mezlocillin in its efficacy against Klebsiella and Serratia. In addition, the β-lactamase stability is better than that of mezlocillin, so that to some extent there is also activity against penicillin-resistant staphylococci.

Example 1 Embodiment A

0.215 mol of ampicillin (anhydrous) are suspended in 1125 ml of anhydrous methylene chloride, the suspension cooled with stirring to 0 to 5 ° C and then fed 0.43 mol of triethylamine with stirring. It is stirred at 5 ° C until a clear solution is obtained. Now, a solution of 0.215 mol of the respective Allophansäurechlorids in 375 ml of mathylene chloride is added at once, wherein the temperature to 15 to 2O ⁰ C increases. The solution is 1.5h. stirred at 20 ° C, then distilling off the methylene chloride in vacuo and the residue dissolved in 500ml of water. The solution is overlaid with 1.61 ethyl acetate, the mixture cooled to 1O ⁰ C and acidified to pH 1.8 with 2N hydrochloric acid with stirring. The phases are separated and the aqueous phase is back-extracted twice with 0.21 ethyl acetate. The vereinigtpi ethyl acetate extracts are now three times with 150ml to pH 2 acidified water and twice with 150ml dist. Washed with water, stirred with 4 to 5 g of activated charcoal and filtered. For conversion into the sodium salt, the filtrate is heated to about 40 ° C and extracted with the calculated amount of an aqueous sodium bicarbonate solution. The aqueous phase is freed from the dissolved ethyl acetate in vacuo, then filtered and lyophilized. Nearly colorless sodium salts are obtained in a yield of 75.0 to 81.0%.

When using 4- (chlorophenyl) -2-methy! -Allophansäurechlorid 97.0 g of sodium salt are obtained when working according to specified instructions, resulting in a yield of 77.6 ^C ,! corresponds to

The compound is characterized by the following values: elemental analysis (C ₂₅ H ₂₅ CIN ₅ NaO ₆ S x 2.5 H ₂ O; MW = 627.045) calc. C = 47.72; H = 4.82; N = 11.13; S = 5.09; H ₂ O = 7,17 gef. 47.66; 4.88; 11.19; 4.91; 7.02 (KF method) IR: (KBr-Presslinga) a _ro (β-lactam) = 1780 cm ^-1 NMR: NMR spectrometer BS 487c from Testa, Brno, 80 MHz

Solvent: DMSO-d ₆ , against HMDS as external standard.

2a, 2β-CH ₃ 1.61 ppm (3H, s) 1.71 ppm (3H, s)

3β-H 4.11 ppm (1 H, s)

5α.6α-Η 5.59 ppm (2H, m)

C ₆ H ₅ -CH- 5.89ppm (1H, J = 7Hz)

C ₆ H ₅ - 7.56 ppm (5 H, m)

CI-C ₆ H ^ - 7.56 ppm (2H, d, J = 9Hz)

7.78 ppm (2H, d, J = 9Hz)

-NH-CH ₃ 3.49 ppm (3H, s)

-NH- 9,32ppm (1H, d, 7Hz)

9.56 ppm (1H, d, 7 Hz) 10.2 ppm (1H, s) TLC: adsorption layer: silica gel GF 254

Mobile phase: water: methanol: pyridine = 40: 160: 8

applied amount: 50g

Drying: 10 min. At 120 ° C

Detection: UV light (254nm)

RF-Wen: 0.7

Example 2 Embodiment A

Allophanoyl-aminobenzylpenicillansäuren

0.215mol ampicillin (anhydrous) are suspended in 1125ml anhydrous methylene chloride, the suspension cooled with stirring to 0 to 5 ⁰ C and then added 0.43 mol of triethylamine with stirring, it is stirred at 50 ⁰ C until a clear solution is.

Now, a solution of 0.215 mol of the respective Allophansäurechlorids in 375 ml of methylene chloride is added all at once, the temperature rises to 15 to 20 ° C. The solution is stirred for 1.5 to 2 hours at 20 ⁰ C, then washed once with 160 ml and then with 88ml of 2N HCl and three times with 160ml of saturated brine. The Mothylenchloridphase is dried over sodium sulfate, filtered and concentrated in vacuo to half. Now, the 2.5 to 3 times the amount (based on the methylene chloride phase used) of petroleum ether, cooled to ^{0 0} C and the methylene chloride solution under vigorous stirring at ^{0 0} C slowly added. This precipitates the free acid of the corresponding Allophanoylaminobenzylpenicillins. The free acid is dried with exclusion of moisture. Yield: 80.8 to 95% d. Th. Based on ampicillin.

Example 3 Embodiment A

1 g of ampicillin (anhydrous) is suspended with stirring in 7 ml of DMF and dissolved by adding 0.2 ml of triethylamine in 1 ml of H ₂ O. Now, with stirring at room temperature, a solution of 0.362 g of 2-methyl-4- (2-chlorophenyl) -allophansäureazid in 8 ml of DMF-added, stirred for 3 to 5 hours and then the DMK was removed in vacuo, the residue with 10 ml of water and 30 ml of ethyl acetate, acidified with 2 N HCl to pH 2 and shaken well, the ethyl acetate layer separated, washed with water and saturated brine, dried and concentrated to dryness in vacuo. There are obtained 0.49 g of N- [4- (2-chlorophenyl) -methyl-allophanyl-amicillin, which corresponds to a yield of 31% of theory.

Example 4 Embodiment B

a) Preparation of N- [4- (3-chlorophenyl) -2-methylallophanoyl] phenylglycine

1 g of D (-) - phenylglycine (6.62 mmol) is suspended in a mixture of 8 ml of THF and 11 ml of water, 1.84 ml (13.24 mmol of triethylamine are added), the solution is cooled to ⁰ ° C. and then a solution of 1 , 63g (6.62 mmol) of 4- (3-chlorophenyl) -2-methylallophanate chloride in 8 to 9 ml of THF are added in one portion The solution is stirred at room temperature for 1 hour, then the THF is distilled off in vacuo, the residue with 10 ml of water and 30ml Essigester added that mixture to 10 ^c C cooled and acidified with 2N HCI to pH2. the phases are separated. the upper organic phase is dried four times with 10 ml of water and washed once with 10 ml of saturated brine and sodium sulfate, evaporated in vacuo to Dry, concentrated to give 1.94 g of a solid residue which is used without purification for further reaction.

b) Preparation of N-KS-chlorophenyl O-methyl-allophanoyl-ampicillin

1.94 g (5,35mmol) of N- [4- (3-chlorophenyl) -2-methyl-allophanoyl) phenylglycine are suspended in 15 ml of THF, dissolved with 0,745ml (5,35mol) of triethylamine, the solution to -2O ⁰ C, 0.51 ml of ethyl chloroformate (5.35 mmol) was added with stirring and stirred at -20 ⁰ C for 30 minutes.

In the meantime, 1.16 g of 6-aminopenicillanic acid are suspended in a mixture of 15 ml of water and 15 ml of THF, dissolved by adding 0.745 ml of triethylamine, the solution cooled to ⁰ ° C. and added to the above solution. The mixture is stirred for 1 hour at 25 ° C, then distilled off the THF in vacuo, the residue with 20ml of water and 50ml ethyl acetate, cooled to 10 ° C and acidified to pH 2 with 2 N NCI. The phases are separated, the upper phase washed three times with 15 ml of water and once with 15 ml of saturated brine and dried with sodium sulfate, distilled off and concentrated to dryness.

Example 5

The efficacy of the new β-lactam antibiotics was demonstrated in the plate diffusion assay on 3 strains of Serratia marcescens from clinical material and 5 penicillin resistant Staph. aureus, also from clinical material, tested. This showed a superiority over the standard mezlocillin (pg / ml)

Serratia marcescens Connect. No. 23 30 50 mezlocillin 20 20 Tribe no. 28 30 1 27 30 31 29 2 28 20.5 21.5 28.5 3 17 17 Staph. aureus (Ptnicillinrestistentsn) Tribe no. 20.5 21 1 20 21.5 22.5 15 2 20 20.5 21 19 3 19.5 21 22.5 15 4 19 20 22.5 16 5 19 12

Further studies on clinical material were performed with 3 E. coli strains, 3 Proteus mirabilis strains, 36 Klebsiella strains, 30 Proteus strains and 30 Pseudomonas aeruginosa strains.

The test substance proved to be more active compared to the tested E. coli strains compared to mezlocillin. Compared with Klebsieila, the test substance performed significantly better in comparison with mezlocillin.

The arithmetic mean values for inhibition zone diameters were 20.6 for the test substance and 16.6 mm for mezlocillin.

Compared with indole-positive proteic strains, the test sub- stance of the comparatively carried carbenicillin was clear

think.

Also over Pseudomonas aeruginosa showed a superiority of the substance 23 in comparison to carbenicillin. The arithmetic mean for the Hemmhofdurchmesser for the test substance was 16.9, for carbenicillin only 8.3.

The test substance shows a stronger effect on E. coli and Proteus mirabilis compared to ampicillin or mezlocillin.

It also has a remarkable Klebsiell effectiveness.

The same applies to indole-positive host strains and Pseudomonas aeruginosa strains. Again, the test substance is much more effective than the reference substance.

Table 1

Position of radicals s. Formula I

No. R ¹ R ² R ³ R ⁴

Ausf. Yield formula form purity

MG

analysis

ber. gef.

1 (4) CI H H CH ₃ (4) HO- H A 92.6 C ₂₆ H ₂₆ CIN ₅ O ₇ S 576.046 C 52.13 52.08 C ₆ H ₅ 96.4 H  1.54 4.31 N 12.16 11.98 2 (2) CI H H CH ₃ C ₆ CH ₅ H A, B 78.3 C ₂₅ H ₂₆ CIN ₅ O ₆ S 560.046 N 12.51 12.38 95.8 3 (3) CI H H CH ₃ C ₆ H ₅ H A ₁ B 83.4 C ₂₅ H ₂₆ CIN ₆ O ₆ S 560.046 N 12.51 12,63 94.6 4 (3) CI (4) CI H CH ₃ C ₆ H ₅ H A 75.8 C ₂₅ H ₂₅ Cl ₂ N ₅ O ₆ S 595.503 C 50.42 50.28 96.2 H 4.23 4.18 N 11.76 11.62 5 (3) CI (4) CI H n-gjhg C ₆ H ₅ H A 75.8 C ₂₉ H ₃₁ Cl ₂ N ₅ O ₆ S 637.584 C 52.75 52.87 93.8 H 4.90 4.85 N 10.99 11.13 6 (4) Br H H CH ₃ C ₆ H ₅ H A 73.7 C ₂₅ H ₂₆ BrN ₅ O ₆ S 604.505 C 49.67 49.54 94.2 H 4.36 4.48 N 4.59 11.47 7 (4) i- H H CH ₃ C ₆ H ₅ H A ₁ B 88.5 C ₂₈ H ₃₃ N ₅ O ₆ S 567.678 N 12.34 12.18 Prop. 93.6 8th (2) CH ₃ (S) CH ₃ H CH ₃ C ₆ H ₅ H A 9C, 1 C ₂₇ H ₃₁ N ₅ O ₆ S 553.651 N 12.65 12.43 97.2 ' 9 (2) CH ₃ O) CH ₃ H nC ₃ H ₇ C ₆ H ₅ H A 33.1 C ₂₉ H ₃₅ N ₅ O ₆ S 581.705 N 12.04 11.83 90.6 10 (2) CH ₃ (4) CH ₃ H CH ₃ C ₆ H ₅ H A 65.98 C ₂₇ H ₃₁ N ₅ O ₆ S 553.651 N 12.65 12.73 95.8 11 O) CH ₃ (4) CH ₃ H CH ₃ C ₆ H ₆ H A ₁ B 67.2 C ₂₇ H ₃₁ N ₅ O ₆ S 553.651 N 12.65 12.38 93.6 12 (2ICH ₃ O H H CH ₃ C ₆ H ₅ H A 75.0 C ₂₆ H ₂₉ N ₅ O ₇ S 555.624 N 12.61 12.47 94.2 13 (2) CH ₃ O H il nC ₃ H ₇ C ₆ H ₅ H A 62.3 C ₂₉ H ₃₅ N ₅ O ₇ S 583.678 N 12,00 ii 'J4 98.4 14 (4) CH ₃ O H H CH ₃ C ₆ H ₅ H A 71.8 C ₂₆ H ₂₉ N ₅ O ₇ S 555.624 N 12.60 12.68 94.6 15 (4) CH ₃ O H H nC ₃ H ₇ C ₆ H ₅ H A 84.4 C ₂₈ H ₃₉ N ₅ O ₇ S 583.673 N 12,00 12.13 95.8 16 (4) CH ₃ O H H nC, H ₉ C ₆ H ₅ H A 95.7 C ₂₃ H ₃ ^ N ₅ O ₇ S 597.705 N 11.72 11.68 96.4 17 (4) CN H H CH ₃ C ₆ H ₅ H A 83.9 C ₂₆ H ₂₆ N ₆ O ₆ S 550.608 N 15.26 15.37 91.8 18 (4) NO ₂ H H CH ₃ C ₅ H ₅ H A 53.8 C ₂₅ H ₂₆ N ₆ OuS 570.597 N 14.73 14.61 96.3 19 (4INO ₂ H H nC ₃ H ₇ C ₆ H ₅ H A 76.2 C ₂₇ H ₃₀ N ₆ O ₈ S 598.651 C 54.17 54.28 96.4 H 5.05 5.17 N 14.04 13.92 20 (2IC ₂ H ₅ (5) NO ₂ H CH ₃ C ₆ H ₅ H A 91.6 C ₂₇ H ₃₀ N ₆ O ₈ S 598.651 C 54.17 54.12 98.3 H 5.05 5.03 N 14.04 14.12 21 (2IC ₂ H ₅ (5) NO ₂ H C ₂ H ₅ C ₆ H ₅ H A 84.6 C ₂₈ H ₃₂ N ₆ O ₈ S 612.678 C 54.89 54.87 96.2 H 5.26 5.41 N 13.72 13.58 22 (2 (C ₂ H ₅ (5) NO. H nC ₃ H ₅ C ₆ H ₅ H A 89.9 C ₂₉ H ₃₄ N ₆ O ₈ S 626.705 C 55.58 55.41 95.8 H 5.47 5.38 N 13.41 13.28

Continuation Table 1

No. R ¹ R ² R ³ R ⁴ AR ⁵ Ex. Yield Formula MW Analysis

form purity over.

23 (4) CI H H CH ₃ C ₆ H ₅ N / A A, B 77.6 C ₂₅ H ₂₆ CIN ₅ NaO ₆ S 582.028 S. example 1 13.14 96.7 24 O) CH ₃ H H CH ₃ C ₆ H ₅ H A 82.3 C ₂₆ H ₂₉ N ₅ O ₆ S 539.624 N 12.98 56.98 94.8 5.10 25 H H H CH ₃ C ₆ H ₅ H A 90.1 C ₂₅ H ₂₇ N ₅ O ₆ S 525.597 C 57.13 13.01 96.2 H 5.18 N 13.33

The numbers given in brackets at R ¹ to R ⁵ and A indicate the position in the ring system.

Tabollö2

Antimicrobial activity of selected compounds in% ampicillin (= 100%), carbenicillin (= 100%), mezlocillin (= 100%)

test organisms Serr. marc. 500 Proteus bulg. Salm. gall. 100 Substance no. Klebs. pneumatic SG 621 500-1000 a x 19 ATCC9184 100 SG117 a) > 500 b) 0 <100 a) <500 200 <100 1 1000 250 > 150 > 10 23 1000 100 200 > 10 3 500 100 150 4 500 > i00 6 300 100 25 75 <500 26 100

a) comparison antibiotics ampicillin

b) comparative antibiotics carbenicillin

c) Vergloichslibiotika mezlocillin

3 71 3

ο u

Claims (3)

A process for the preparation of novel ailophanoyl-aminobenzylpenicilines of general formula I, wherein R ¹ , R ² = H, halogen, lower straight-chain or branched alkyl or alkoxy, alkylthio, Alkylsulfonyl, carboxy, cyano, nitro, amino or SO ₃ H groups R ³ , R ⁴ = H, lower straight-chain or branched alkyl groups A = phenyl radical, partially or fully hydrogenated, optionally substituted R ⁵ = a physiological compatible cation or an easily cleavable under physiological conditions ester group characterized in that substituted allophanic acids or derivatives of the general formula II in which B is an activated F ^: orm of the carboxyl group and the other substituents have the meaning given, either directly with molar amounts of an aminobenzylpenicillin whose 3-carboxyl Group is blocked, in the presence of a proton acceptor, be reacted at temperatures between 0 and 2O ⁰ C in an inert anhydrous or aqueous solvent or solvent mixture or are reacted under comparable conditions with an amino acid of the formula III whose carboxyl group is temporarily blocked, and then activates the carboxyl group of the newly formed compound and the reaction product is reacted with e-Amiuc'penicillansäure. 2. The method according to item 1, characterized in that the reaction is preferably carried out at temperatures between 5 to 15 ° C. 3. The method according to item 1 and 2, characterized in that preferably the D (-) - form of the amino acid is used.