DE2612926A1 - Broad spectrum antibacterial hydantoinyl-acetyl-ampicillin derivs. - prepd. by reacting hydantoinyl-acetic acids with phenyl-glycine and (6)-amino-penicillanic acid - Google Patents

Abstract

New penicillin derivs. are cpds. of formula (I) and their acceptable salts. In formula (I), R1 is H, lower alkyl, aralkyl or aryl opt. substd. by a halogen atom; and R2 and R3 are H or lower alkyl. Specific cpds. (I) include D-alpha- (5,5-dimethyl-hydantoin-1-yl)-acetamido -benzylpenicilli- n. In an example, this is prepd. by reacting (5,5-dimethylhydantoin-1-yl)acetic acid with SOCl2 to give the acid chloride, and reacting this with N-trimethylsilyl-ampicillin trimethylsilyl ester. The product is isolated in the form of its potassium salt. (I) are useful against gram-positive and negative organisms, esp. those of the genus Pseudomonas.

Description

New acyl derivatives of 6- (a-amino-phenylacetamido) -penicillanic acid

Well-known 6-a-aminoacylpenicillanic acids, such as ampicillin, amoxycillin, Epicillin, and Cyclacillin, are valuable antibiotics that stimulate the growth of a broad Effectively inhibit spectrum gram-positive and gram-negative bacteria. These penicillins however, do not have any significant activity against bacteria of the Pseudomonas group on. The well-known penicillins carbenicillin and sulbenicillin are effective against gram negative germs including Pseudomonas. Because of that, however, still relatively low activity, they must be administered in high doses. Also wise Carbenicillin and sulbenicillin when given orally because of poor absorption very limited effectiveness in the gastrointestinal tract.

The object of the present invention is to penicillin derivatives with a broad spectrum of activity against gram-positive and gram-negative germs, in particular to provide those of the genus Pseudomonas.

The present invention therefore relates to penicillin derivatives of the general formula I in which R1 is a hydrogen atom, a lower alkyl, an aralkyl or an aryl group optionally substituted by a halogen atom, R2 and R3, which may be the same or different, each represent a hydrogen atom or a lower alkyl group, the pharmacologically acceptable ones Salts, processes for the preparation of the compounds according to the invention and pharmacological preparations containing substances of the general formula I.

Due to the additional asymmetric carbon atom of the acyl side chain, the new compounds exist in epimeric D and L forms. The invention includes both the D- and L-epimers of the general formula I and mixtures thereof.

It has been found that the new compounds of the general formula I have an excellent antibacterial effect against both gram positive and also against gram-negative germs, especially those of the genus Pseudomonas, have and therefore particularly advantageous for combating bacterial infectious diseases can be used.

The lower alkyl groups in the definitions of the substituents R1, R2 and R3 can be straight-chain or branched and 1 to 5, in particular 1 to Contains 3 carbon atoms. The methyl group is particularly preferred.

Under an aralkyl group is preferably a benzyl radical and under an aryl group is preferably to be understood as a phenyl radical. As are halogen atoms Fluorine, chlorine and bromine atoms, but especially fluorine and chlorine atoms are preferred.

As pharmaceutically acceptable salts of the compounds according to the invention the alkali metal, alkaline earth metal, aluminum, ammonium and substituted ones Ammonium salts derived from amines such as procaine, dibenzylamine, N, N-dibenzylethylenediamine, N-ethylpiperidine and triethylamine / preferred.

The compounds of general formula I are prepared in a manner known per se; In particular, it is characterized in that a carboxylic acid of the general formula II is obtained by methods of peptide chemistry known per se in which R1, R2 and R3 have the meaning given above, or a reactive derivative thereof is reacted with phenylglycine and 6-aminopenicillanic acid and the compounds of general formula I obtained are converted, if desired, into pharmacologically acceptable salts.

It is possible to first allow a carboxylic acid of the general formula II or a reactive derivative thereof to react with phenylglycine and the resulting compound of the general formula III in which R1, R2 and R3 have the meaning given above, - optionally after conversion of the carboxyl function into a reactive derivative with 6-aminopenicillanic acid to convert to compounds of the general formula I, the carboxyl group of phenylglycine in the first sub-step and the Carboxyl function of 6-aminopenicillanic acid is to be protected as an intermediate.

You can also first let phenylglycine react with 6-aminopenicillanic acid and the resulting compound of formula IV with a carboxylic acid of general formula II or a reactive derivative thereof to form compounds of general formula I, the amino group of phenylglycine and the carboxyl function of 6-aminopenicillanic acid in the first sub-step and the carboxyl function of a-aminophenylacetamido-penicillanic acid in the second sub-step Formula IV is to be protected as an intermediate.

As reactive derivatives of carboxylic acids of the general formulas II and III are preferably acid halides, especially chlorides and bromides, mixed anhydrides with carbon mono-lower alkyl esters, especially ethyl or Isobutyl esters or active esters, especially p-nitrophenyl, 2,4, 5-trichlorophenyl, pentachlorophenyl, N-hydroxysuccinimide ester is used.

The free carboxyl group of phenylglycine, α-aminophenylacetamido-penicillanic acid of the formula IV or 6-aminopenicillanic acid can be obtained by introducing a carboxyl protective group or by salt formation with an inorganic or a tertiary organic Base, such as triethylamine. Leave as carboxyl protecting groups use the easily cleavable esters commonly used in peptide chemistry (cf. on this: Houben-Weyl, Methods of Organic Chemistry, Vol. 15/1). Preferred are silyl esters (e.g. trimethylsilyl ester), stannyl esters (e.g. tri-n-butyltin ester), Benzyl or substituted benzyl esters and p-bromophenacyl esters.

When using a trialkylsilyl radical as a carboxyl protective group such derivatives of phenylglycine of 6-aminopenicillanic acid or a Compounds of the formula IV are used which, in addition to the carboxyl group, are also used carry a trialkylsilyl radical on the nitrogen atom of the primary amino group.

The one in the reaction of phenylglycine with 6-aminopenicillanic acid necessary protection of the amino group of phenylglycine is achieved by introducing a Amino protective group commonly used in peptide chemistry, e.g. of the carbobenzoxy radical, or caused by salt formation with a suitable inorganic or organic acid.

The reactions for the preparation of the substances according to the invention take place in a manner known per se in peptide chemistry, such as those in Houben-Weyl, methods of Organic Chemistry, Vol. 15/2, are explained in more detail. Preferably the Acylation reactions in inert organic solvents, for example methylene chloride, Acetone, ethyl acetate, Acetonitrile, dimethylformamide, tetrahydrofuran, Dioxane or mixtures thereof, at temperatures from -7O0C to + 1000C, preferably between -3O0C and + 10 ° C.

In any partial step, the carboxyl group of the amine components Protected by salt formation, the reaction with the carboxylic acid components can take place can also be carried out in water as a solvent, if as a reactive derivative of the latter, a carboxylic acid chloride or a mixed anhydride is used.

If the carboxylic acid component is used as a free carboxylic acid, so the amide bond using a carbodiimide, e.g. dicyclohexylcarbodiimide, be knotted.

In the event that as a reactive derivative of the carboxylic acid components a carboxylic acid chloride is used, this can be particularly advantageous from the free carboxylic acid and thionyl chloride in hexamethylphosphoric triamide according to a by J.F. Normant and H. Deshayes in Bull. Soc. Chim.

Fr. 1972, 2854, method described and without isolation be reacted with the carboxyl-protected amine components. The usual addition a base, e.g. a tertiary amine, e.g. triethylamine, N-methylmorpholine or N, N-dimethylaniline, is unnecessary as the solvent is hexamethylphosphoric triamide intercepts the resulting hydrogen chloride.

The cleavage of the protective groups after the reaction has taken place in be carried out in the usual way. E.g.

a trialkylsilyl radical used as a carboxyl protecting group below particularly mild conditions by treating the reaction product with water or lower alcohols can be removed. Benzyl esters can be catalytic Hydrogenation split off by means of a noble metal catalyst, e.g. palladium-carbon. One as Trialkyltin ester or phenacyl ester protected carboxyl group can be replaced by potassium or sodium thiophenolate may be released. For example, by the carbobenzoxy radical Protected amino group of phenylglycine can after the reaction by catalytic Hydrogenation can be converted into the free amino group.

The carboxylic acids used as starting materials of the general Formula II have not yet been described either.

They can be prepared by methods known per se. For example, a carboxylic acid of the general formula II can be obtained by treating an isocyanate of the general formula V R1-N = C = O (V), in which R1 has the meaning given above, with a Iminodiacetic acid derivative of the general formula VI in which R2 and R3 have the meaning given above, to the corresponding ureido compound of the general formula VII in which R1, R2 and R3 have the meaning given above, which is then converted into a hydantoin derivative of the general formula II by cyclization.

Instead of an iminodiacetic acid derivative of the general formula VI can also be a corresponding ester, diester, nitrile, dinitrile or mixed Ester nitrile derivative can be used. In this case it is necessary to use im Following the cyclization, the ester obtained or the nitrile formed To saponify compound of general formula II in the usual way acidic or alkaline.

The cyclization of compounds of the general formula VII takes place in a manner known per se, e.g. by boiling with aqueous mineral acid, for example Hydrochloric acid.

When using an asymmetrically substituted iminodiacetic acid of the general formula II or an ester or nitrile derivative thereof can be isomers arise which result from the position of the substituents R2 and R3 on the ring or differ in the side chain. By choosing a suitable ester, nitrile or mixed ester-nitrile derivatives, the cyclization can to a certain extent so be directed that preferably the desired hydantoin-acetic acid derivatives of general formula II with the substituents R2 and R3 are formed on the ring.

In this way, hydantoin acetic acids of the general Preparing formula II in which R1 is an optionally halogen-substituted aryl radical introduces.

For this purpose, halogen-substituted aryl isocyanates are used, if appropriate in aqueous, neutral solution with iminodiacetic acids of the general formula VI and after the cyclization by boiling with aqueous hydrochloric acid it is obtained directly desired carboxylic acid of the general formula II.

Furthermore, for the preparation of a carboxylic acid of the general formula II a (hydantoin-l-yl) optionally mono- or disubstituted in the 5-position acetic acid esters, e.g. the (hydantoin-1-yl) -acetic acid ethyl ester, which is described in J. Amer. Chem.

Soc. 37, 935 (1915) is described, in a manner known per se with Alkyl halides, especially bromides or iodides, on the imide nitrogen (in the 3-position) be alkylated. For the alkylation of hydantoins see Chem. Revs. 46, 403 (1950) and J. Med. Chem. 16, 955 (1973).

Another process for the preparation of compounds of the general formula II, in particular those in which R1 is a hydrogen atom, starts from hydantoins of the general formula VIII, in which R2 and R3 have the meaning given above and R has the same meaning as R1 with the exception of a hydrogen atom or represents a protective group which enables clear alkylation on the nitrogen atom in the l-position.

These hydantoin derivatives are converted in a manner known per se with sodium hydride in a polar, aprotic solvent, e.g. dimethylformamide, and subsequent reaction with a haloacetic acid ester, preferably ethyl bromoacetate, alkylated on the nitrogen atom in the l-position [cf. on this J.C.S. Perkin I 219 (1974) j.

Substituted aminomethyl groups, which serve as protective groups R by aminomethylation with formaldehyde and a secondary amine, e.g. piperidine or morpholine, introduced selectively in the 3-position of the hydantoin [cf. For this Tetrahedron 15, 93 (1961) and Experientia 21, 508 (1965)] and following the Alkylation reaction can be removed again by mild, acidic hydrolysis. The hydrolysis of the ester group takes place in a known manner by alkaline saponification, e.g. with ethanolic potassium hydroxide.

To convert the compounds of general formula I into their pharmacologically acceptable salts are used in a manner known per se with metal salts of suitable acids, e.g. sodium hydrogen carbonate, potassium 2-ethyl-hexanoate, or with suitable organic amines, e.g. triethylamine or N-ethylpiperidine, around.

The compounds according to the invention are used for the production of medicaments of the general formula I or their pharmacologically acceptable salts per se known manner with suitable pharmaceutical carrier substances, aroma, taste and dyes mixed and shaped, for example, as tablets or dragees or with the addition of appropriate auxiliaries in water or oil, such as olive oil, suspended or dissolved.

The new substances I according to the invention and their salts can be used in liquid or solid form can be administered parenterally.

The injection medium used is preferably water, which the usual additives for injection solutions such as stabilizers and solubilizers or contains buffers.

Such additives are e.g. tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts), high molecular weight Polymers (such as liquid polyethylene oxide) to regulate viscosity. Solid carriers are e.g. starch, lactose, mannitol, methyl cellulose, Talc, highly dispersed Silicic acids, higher molecular fatty acids (such as stearic acid), gelatine, agar-agar, Calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight Polymers (such as polyethylene glycols), preparations suitable for oral administration may contain flavors and sweeteners if desired.

For the purposes of the present application, preference is given to those in the The following compounds mentioned the following examples: D-a {[3- (4-fluorophenyl) -hydantoin-1-yl] -acetamido} -benzylpenicillin D-α {[3- (4-chlorophenyl) hydantoin-1-yl] acetamdo} benzyl penicillin.

The invention is illustrated in more detail by the following examples.

Example 1 D ~ a - [(5,5-Dimethylhydantoin-1-yl) -acetamido] -benzylpenicillin 1.5 g of (5,5-dimethylhydantoin-l-yl) acetic acid are dissolved in 10 ml of hexamethylphosphoric acid triamide and 5 ml of methylene chloride dissolved. After cooling to -10 ° C, the mixture is added dropwise with 0.96 g of thionyl chloride in 5 ml of methylene chloride. The clear solution stirs 45 minutes at -100C and then a solution of N-trimethylsilyl-ampicillintrimethylsilyl ester is added dropwise (made from 2.8 g of anhydrous ampicillin and 1.73 g of trimethylchlorosilane) in Methylene chloride too. The reaction mixture is stirred for one hour at -100C and then warmed to room temperature. The methylene chloride is distilled off in vacuo, the residue with 45 ml of saturated sodium hydrogen carbonate solution while cooling with ice offset. It is extracted with ethyl acetate, the aqueous phase is acidified to pH 2 and extracted again with ethyl acetate. The ethyl acetate extract is washed with water, dried and then treated with 5 ml of 2 N potassium ethylhexanoate solution in tetrahydrofuran. The precipitate which separates out is filtered off. 2.5 g (56% per hour) of potassium salt are obtained of D-a - [(5,5-dimethylhydantoin-1-yl) -acetamido] -benzyl-penicillin of melting point 214 - 2170C (with decomposition).

The (5,5-dimethylhydantoin-lyl) acetic acid used as the starting substance is prepared as follows: 110 g of 5,5-dimethyl-3-morpholinomethyl-bydantoin (0.474 mol) are dissolved in 400 ml of dry dimethylformamide and added in portions with 14.5 g sodium hydride suspension in mineral oil offset. After about 2 hours 100 g (0.6 mol) of ethyl bromoacetate are added to the solution with cooling. The mixture is left to stir at room temperature and finally to stand for 24 hours. The reaction mixture is mixed with water and the morpholinomethyl group is split off acidified with 2N hydrochloric acid. The solution is extracted with ethyl acetate and the organic phase dried and evaporated. The crude product is made with methyl isobutyl ketone digested and the precipitate filtered off with suction. 30 g (30% of theory) are obtained (5,5-dimethyl-hydantoin-1-yl) -acetic acid ethyl ester.

M.p .: 169-170 ° C.

15.8 g (0.05 mol) of barium hydroxide are dissolved in 400 ml of water and with 21.4 g (0.1 mol) of ethyl 5,5-dimethylhydantoin-l-ylacetate Stirring is heated for 3.5 hours. After cooling, it is extracted with ethyl acetate.

The aqueous phase is mixed with 80 ml of 2 N sulfuric acid while hot, the precipitated barium sulfate is filtered off and the filtrate becomes dry evaporated. The crude product is recrystallized from tetrahydrofuran / methyl isobutyl ketone.

14.5 g (78% of theory) (5,5-dimethylhydantoin-1-yl) acetic acid are obtained. M.p .: 196-2120C.

Example 2 D-a-t (3-Phenylhydantoin-1-yl) -acetamido] -benzylpenicillin 2.34 g of (3-phenylhydantoin-l-yl) acetic acid are suspended in 200 ml of methylene chloride and brought into solution by adding 1.02 g of N-methylmorpholine. After cooling down on -200C the mixture is added dropwise with 1.44 g of isobutyl chloroformate added and stirred at -150C for 30 minutes.

A solution of N-trimethylsilylampicillin trimethylsilyl ester is then added dropwise in methylene chloride (prepared from 3.49 g of anhydrous ampicillin and 2.17 g Trimethylchlorosilane). The reaction mixture is stirred for 2 hours at -150C and then warmed to room temperature.

The methylene chloride is stripped off and the residue is taken up in ethyl acetate and 80 ml of half-concentrated sodium hydrogen carbonate solution are added. The organic The phase is separated off and the aqueous phase is acidified to pH 2 with dilute hydrochloric acid. The reaction product is extracted with ethyl acetate and the extract is dried with anhydrous Sodium sulfate and 5 ml of 2N potassium ethylhexanoate solution in tetrahydrofuran are added dropwise to. The precipitate which separates out is filtered off. 3.1 g (51% of theory) of potassium salt are obtained of D-a - [(3-phenylhydantoin-l-yl) -acetamido] -benzyl-penicillin with a melting point of 196 - 198 ° C (with decomposition).

The (3-phenylhydantoin-l-yl) acetic acid used as the starting substance is prepared in the following manner: 33.2 g (0.25 mol) of iminodiacetic acid and 30.8 g (0.55 mol) of potassium hydroxide are dissolved in 100 ml of water. While stirring vigorously 33 g (0.275 mol) of phenyl isocyanate are added dropwise over the course of 4 hours. the The mixture is stirred for a further 2 hours at room temperature and left to stand overnight. The deposited precipitate is filtered off and washed with 50 ml of water. Filtrate and wash water are mixed with 250 ml of concentrated hydrochloric acid and 1 hour refluxed.

The mixture is then cooled with ice. The unusual Crystals are filtered off and dried in a vacuum desiccator. The raw product (53.5 g) is recrystallized from ethanol. 45 g (77% of theory) of 3-phenylhydantoin-1-yl) acetic acid are obtained. M.p. 204-2060C.

Example 3 D <- [(3-Benzythydantoin-1-yL) -acetamido] -benzylpenicillin From 2.48 g (3-benzylhydantoin-L-yl) acetic acid and the equimolar amount of N-trimethyl Iyl ampicillin trimethylsilyl esters are prepared according to that described in Example 2 Procedure 3.99 g (65% of theory) potassium salt of de - [(3-benzyl-hydantoin-L-yl) -acetamido] -benzylpenicillin of m.p. 183-1850C (with decomposition).

The (3-benzylhydantoin-1-yL) acetic acid used as the starting substance is prepared in the following way: A solution of 12.1 g (65 mmol) (hydantoin-l-yl) -acetic acid ethyl ester in 325 ml of distilled dimethylformamide is added with stirring with 1.96 g (65 mmol) Sodium hydride added. When the salt formation has ended, 11.15 g (65 mmol) of benzyl bromide are obtained added and the reaction mixture was heated to 100 ° C. for 4 hours.

Then the dimethylformamide is distilled off, the residue with water added and the product extracted with ethyl acetate.

After the ethyl acetate has been distilled off, an oil is obtained which after crystallized after inoculation. This gives 18.1 g (100% of theory) (3-benzylhydantoin-l-yl) ethyl acetate.

Mp 70 ° C.

18 g (65 mmol) (3-benzylhydantoin-l-yl) -acetic acid ethyl ester a solution of 3.65 g (65 mmol) of potassium hydroxide in 75 ml of ethanol is added. The ester goes into solution with heating. It is left to stand overnight and evaporated to dryness in, mixed with water and etherified out. The aqueous phase is acidified with a lot of ethyl acetate extracted, the extract is dried and evaporated. The remaining Oil becomes with ether rubbed. The product crystallizes out. To after filtering off and washing with ligroin, 12.0 g (75% of theory) of (3-benzylhydantoin-1-yl) acetic acid remain. M.p. 90-920C.

Example 4 D-a - [(3-Methylhydantoin-1-yl) -acetamido] -benzylpenicillin From 3.44 g of (3-methylhydantoin-l-yl) acetic acid and the equimolar amount of N-trimethyl Silyl ampicillin trimethylsilyl esters are prepared according to that described in Example 2 Procedure 6.6 g (61% of theory) potassium salt of D-a - [(3 ethylhydantoin-ivl) -acetamido] -benzylpenicillin of melting point 198-2000C (with decomposition> obtained.

The (3-methylhydantoin-l-yl) acetic acid used as the starting product is prepared as follows 3 g of an 8OYoigen sodium hydride suspension are made by Wash with petroleum ether and remove mineral oil with 50 ml of dried dimethylformamide offset. 11.4 g (0.1 mol) of 3-methylhydantoin are added with stirring. After an hour 20 g (0.12 mol) of ethyl bromoacetate are stirred in the course of one hour added dropwise. The mixture is stirred for a further 3 hours and left to stand overnight. At the the next day 25 ml of hydrogen chloride and 10 ml of water are added. It goes the existing precipitate in solution. It is extracted twice with ethyl acetate and the ethyl acetate extract washed thoroughly with water. After drying and Evaporation of the organic phase gives 18.2 g (91% of theory) (3-methylhydantoin-1-yl) -acetic acid ethyl ester as a yellowish oil.

31 g of (3-methylhydantoin-l-yl) -acetic acid ethyl ester are stirred with stirring at room temperature with a solution of 11.2 g of potassium hydroxide in 230 ml of ethanol offset. After stirring for three hours, the mixture is evaporated to dryness, dissolved in water and extracted with ethyl acetate. The aqueous phase is treated with 6 N hydrochloric acid acidified and extracted a total of twelve times with ethyl acetate. The combined ethyl acetate phases after evaporation and drying give 8.6 g of crude product. After recrystallization 5.5 g (21% of theory) of (3-methylhydantoin-1-yl) acetic acid are obtained from methyl isobutyl ketone. M.p. 122-1240C.

Example 5 D-a - [(3,5,5-Trimethylhydantoin-1-yl) -acetamido] -benzylpenicillin From 3.0 g (3,5,5-trimethylhydantoin-1-yl) acetic acid and the equivalent amount N-Trimethylsilyl-ampicillin-trimethylsilyl esters are prepared according to that described in Example 2 Procedure 7.4 g (87% of theory) potassium salt of D-a - [(3,5,5-trimethylhydantoin-1-yl) -acetamido] -benzylpenicillin of m.p. 186-1890C (with decomposition).

The (3,5,5-trimethylhydantoin-lyl) acetic acid used as the starting substance is prepared in the following way: 7.5 g (5, 5-dimethylhydantoin-l-yl) -acetic acid ethyl ester (Production described in Example 1) are dissolved in 37.5 ml of dimethylformamide and 1.05 g of sodium hydride in mineral oil (suspension above) in portions with stirring added. The mixture is left for one hour to complete the salt formation stirred at room temperature and then added dropwise with 7.1 g Methyl iodide offset. After stirring for two hours at room temperature, the reaction mixture becomes heated to 800 for 45 minutes and, after cooling, mixed with water. The clear one The solution is extracted with ethyl acetate, the extract is washed with water and dried and evaporated. About 7 g of a yellowish oil remain, which can be cleaned without cleaning is further processed. A solution of 2.25 g of potassium hydroxide is added to the oil in 46 ml of ethanol, the mixture is stirred for 3 hours at room temperature and concentrated to dryness a. The residue is dissolved in water and the solution is extracted with ethyl acetate. The aqueous phase is adjusted to pH 1-2 and extracted several times with ethyl acetate. The combined extracts are dried and the solvent is distilled off. The remaining oil crystallizes after trituration with methyl isobutyl ketone and ligroin. 3.9 g (56% of theory) (3,5,5-trimethylhydantoin-1-yl) acetic acid are obtained of m.p. 118-1200C.

Example 6 D-a- [(3-Phenylhydantoin-1-yl) -acetamido] -benzylpene ic illin From 3.67 g of N - [(3-phenylhydantoin-l-yl) -acetamido] -D-phenylglycine and the equivalent amount of N-trimethylsilyl-6-amino-penicillanic acid trimethylsilyl ester according to the procedure described in Example 2, 2.9 g (48% of theory) of potassium salt of D-a - [(3-phenylhydantoin-1-yl) -acetamidoi-benzylpenicillin of m.p. 194-1970C (with decomposition) obtained.

The N - [(3-phenylhydantoin-1-yl) acetamido] -D-phenylglycine used as the starting product is made in the following way: 2.34 g (3-phenylhydantoin-1-yl) acetic acid (Preparation described in Example 2) are in 20 ml of dry methylene chloride and 102 g of N-methylmorpholine dissolved. The solution is cooled to -200C and added dropwise 1.44 g of isobutyl chloroformate were added. After 45 minutes of stirring at -150C an equivalent amount of N-trimethylsilyl-D-phenylglycine trimethylsilyl ester [cf. Synthesis 420 (1974)] was added dropwise in dry methylene chloride. The reaction mixture is stirred for 2 hours at -10 ° C, warmed to room temperature and evaporated.

The residue is dissolved in 45 ml of saturated sodium hydrogen carbonate solution taken up, the solution extracted with ethyl acetate, the aqueous phase separated and acidified to pH 2 with dilute hydrochloric acid. The falling precipitate will Aspirated, washed well with water and dried. 2.76 g (75% of theory) are obtained N- [(3-phenylhydantoin-1-yl) acetamido] -D-phenylglycine. A sample is made from ethanol recrystallizes and melts at 175 - 1770C.

Example 7 D-a - [(3-n-Propylhydantoin-1-yl) -acetamido] -benzylpenicillin From 2.0 g of (3-n-propylhydantoin-1-yl) acetic acid and the equivalent amount of N-trimethylsilyl-ampicillin-trimethylsilyl ester 2.4 g (80% of theory) of potassium salt are obtained according to the procedure described in Example 2 of D-a - [(3-n-propylhydantoin-l-yl) -acetamido] -benzylpenicillin of melting point 185-187 & (with decomposition) obtained.

The (3-n-propylhydantoin-ly4-acetic acid obtained by alkylating the (hydantoin-lyl) -acetic acid ethyl ester with n-propyl iodide and subsequent saponification of the resulting (3-n-propylhydantoin-l-yl) -acetic acid ethyl ester analogous to the process described in Example 5 for the preparation of 1- (1,5,5-trimethylhydantoin) acetic acid. The carboxylic acid is obtained as a slightly yellowish oil and is used for isolation Reaction with 16 ml of 2 N potassium ethylhexanoate converted into the potassium salt. M.p. 120 - 1220C.

Claims (4)

Patent claims 1. Penicillin derivatives of the general formula I in which R1 is a hydrogen atom, a lower alkyl, an aralkyl group or an aryl group optionally substituted by a halogen atom, R2 and R3, which can be identical or different 3 ', each denote a hydrogen atom or a lower alkyl group, and their pharmacologically acceptable salts. 2. Process for the preparation of penicillin derivatives of the general formula I. in which R1 is a hydrogen atom, a lower alkyl, an aralkyl or an aryl group optionally substituted by a halogen atom, R2 and R3, which may be the same or different, each represent a hydrogen atom or a lower alkyl group, and pharmacologically Compatible salts, characterized in that, according to methods of peptide chemistry known per se, a carboxylic acid of the general formula II in which R1, R2 and R have the meaning given above, or a reactive derivative thereof is reacted with phenylglycine and 6-aminopenicillanic acid and the compounds of general formula I obtained are converted, if desired, into pharmacologically acceptable salts. 3. Use of substances of general formula I and their pharmacological use compatible salts for the manufacture of drugs with an antibacterial effect. 4. Medicaments consisting of compounds according to claim 1 and customary Carriers and auxiliary materials.