DE2066157C2 - Acylureidopenicillins - Google Patents

Description

The invention relates to acylureidopenicillins in which the hydrogen atom is in the 3-position located nitrogen atom is substituted by other radicals

6 - {«- 3-AcylureidophenyIacetamido) penicillanic acids are in Dutch patents 69.01646 and 69.08909 and US patents 34 79 339 and 34 81 922 but all have 3-acylureidophenylacetamidopenicillanic acids described and claimed in these patents in the acylureido group on the nitrogen atom in the 3-position Hydrogen atom. The presence of this hydrogen atom and the absence of any other substituent at this point the acylureido group inevitably results from the different synthetic route these penicillins.

The invention also relates to a process for the preparation of such compounds which are used in the treatment of infections caused by gram-positive and gram-negative germs, in particular by Klebsiella aerobacter strains, to provide valuable help at low doses.

The compounds according to the invention and their non-toxic, pharmaceutically acceptable salts correspond in the acid form to the general formula

A-CO-NH-CH-CO-NH-CH-CH

-N

CH

CH ₃

CH ₃

COOH

in the

B phenyl and

A-CO-NH- a (3-acetyl-3-allylureido) - or (3-y-chlorobutyryl-3-methylureido) -or (3-isopropoxycarbonyl-3-methylureido) - or (3-Cyclohexyloxycarbonyl-S-methylureidoJ- or β-allyloxycarbonyl-3-methylureido) - or [3- (2-thenoyl) -3-methylureido] or [3- (3,5-dimethylisoxazoloyl-4) -3-methylureido] or (3-n-butoxycarbonyl-3-methylureido) group or

B p-methylphenyl and

A-CO-NH- a (3-benzoyl-3-methylureido) group or

B 2-thienylund

A-CO-NH- a p-γ-chlorobutyryl-S-methylureido) group represent and with respect to the chiral center C * one of the two possible Can be diastereomers with the R or S configuration or as mixtures of the two Diastereomers can exist,

as well as their non-toxic, pharmaceutically acceptable salts.

The compounds of the invention are prepared by adding 6-aminopenicillanic acid (Formula II) or compounds of the general formulas HI and IV

45

50

55

60 CH ₃
H ₂ N-CH-CH \ /

I I c (Π)

C N / \

/ \ / CH ₃

O CH

COOH

CH ₃

H ₂ N-CH-CH

(ΠΙ)

R ₇

R ₈ -Si-NH-CH-CH

/ I I

^C \

means R _{n is} a divalent organic radical
- (CH ₂ ) ^ -,
or

CH

/ ίο represents and W is halogen, in an anhydrous, O Si Rj indifferent organic solvent in the presence N of about one molar equivalent of a base for a

Brings 60 ° C to +30 ⁰ C for reaction, or by reacting the carboxylic acids of general (IV) 15 my formula V into the corresponding carboxylic acid derivatives of general formula IX - R9 temperature of about

wherein R ₇ , R ₈ and R ₉ denote alkyl with up to 6 carbon atoms, with carboxylic acids of the general formula V modified at the carboxyl group

A-CO-NH-CH-COOH
B.

in which A — CO — NH—, B and C * have the meaning given above, in the case of using the compounds of the general formula II in anhydrous or water-containing solvents in the presence of a base, in the case of using the compounds of the general formulas III and IV in anhydrous and hydroxyl-free solvents has to react with or without the addition of a base at a temperature in the range of about -20 ⁰ C to +50 ⁰ C. in this case, the change of the carboxyl group of the carboxylic acids of the general formula V is obtained by reacting either of these carboxylic acids with about one molar equivalent of the compounds of the general formulas VI, VII or VIII

R9

9 \

R ₉

= C-N

R.

I. W.

R ₁

(VI)

W ^e

(VIf)

₁ ^ C- N

CH ₂ CH ₂ '

CH ₂ CW

N
Rio

wherein R _{9 has} the meaning given above, R ₁₀ either has the same meaning as R 1 or phenyl

W ^e

(Vffl)

A-CO-NH-CH-C

I.
B.

O-N = C

(IX)

wherein A - CO - NH -, B and C * are those given above Have meaning and Q is the radical -CN and / or -COO-lower alkyl, transferred. For the production of the carboxylic acid derivatives of the general formula IX one starts from the compounds of the general Formula X off,

HO-N = C

(X)

wherein Q has the meaning given above, which in an anhydrous, inert organic solvent in the presence of at least one molar equivalent of a tertiary organic base at temperatures of about -25 ⁰ C to +25 ⁰ C with one mol equivalent of thionyl chloride to form one molar equivalent of base hydrochloride in not known Zwischenverbindüngen be converted, which are then reacted, without isolation, in the presence of a further molar equivalent of a base with a molar equivalent of the carboxylic acids of the general formula V at a temperature of about -25 ° C to +25 ⁰ C to the carboxylic acid derivatives of general formula IX.

The non-toxic pharmaceutically acceptable salts mentioned above include salts of the acidic carboxyl group such as the sodium, potassium, magnesium, calcium, aluminum and ammonium salts, and non-toxic substituted ammonium salts with amines such as di- and tri-lower alkyl amines , Procaine, dibenzylamine, Ν, Ν'-dibenzylethylenediamine, N-benzylβ-phenylethylamine, N-methyl- and N-ethylmorpholine, 1-ephenamine, dehydroabietylamine, N, N'-bis-dehydroabietylethylenediamine, N-lower alkylpiperidine and other amines have been used to form salts of penicillins.
With the expression "lower alkyl" is in the

present invention as both a straight chain also understood to be a branched alkyl group with up to 6 carbon atoms.

In the reaction according to the invention of the carboxylic acids of the general formula V with 6-aminopenicillanic acid, those at the carboxyl group are changed Carboxylic acids preferably in the form of a solution in an anhydrous, inert organic solvent with a solution of 6-aminopenicillanic acid in Water, hydrous or anhydrous organic solvents brought together in the presence of a base as a solvent for those attached to the carboxyl group Modified carboxylic acids are suitable, for example, for a water-containing reaction medium acetone, Tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide and hexamethylphosphoric acid triamide for one anhydrous reaction medium, preferably methylene chloride and chloroform.

The 6-aminopenicillanic acid is preferably used as a solution of its salt with a base in water or in a mixture of water with a water-miscible solvent or in an anhydrous one organic solvents used in the reaction according to the invention Suitable solvents, except Water, for a water-containing reaction medium, are preferably acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide and isopropanol anhydrous reaction medium in addition to the solvents mentioned, preferably methylene chloride and chloroform. To convert the 6-aminopenicillanic acid into the salt of a base dissolved in a solvent can be used as suitable bases in the case of an aqueous or water-containing reaction mixture, for example, inorganic bases such as sodium carbonate, sodium hydroxide, sodium bicarbonate, the corresponding potassium and calcium compounds, magnesium oxide or magnesium carbonate or buffer mixtures, in the case of an anhydrous reaction medium preferably triethylamine, pyridine, diethylamine, Use N-Ethylpiperi-iin or N-Ethylmorpholine.

The inventive reaction with modified carboxylic acids of the general formula V, with the silylated 6-aminopenicillanic acids of the general formulas III and IV is in hydroxyl group-free, indifferent organic solvents, for example in carbon tetrachloride, Methylene chloride, chloroform, tetrahydrofuran, benzene, Run diethyl ether or benzene

The reaction according to the invention of the carboxylic acids of the general formula V, in the form modified at the carboxyl group, with δ-aminopenicilanic acid in an aqueous or water-containing medium, at a pH of preferably 6.5 to 8.0 or even at a pH of about 3 can be carried out.

As with most chemical reactions, temperatures can be higher or lower than those in the Examples given can be used. However, if one goes well beyond the values given there In addition, there will be an increasing number of side reactions which reduce the yield or which Adversely affect the purity of the products. On the other hand, excessively lowered reaction temperatures reduce the reaction rate so much that Reductions in yield can occur. There are therefore in the implementation according to the invention at the Carboxyl group modified carboxylic acids of the general formula V with the 6-aminopenicillanic acid or the silylated 6-Aminopenicillansäuren of the general formulas IV and IH reaction temperatures from -20 ⁰ C to 3O ⁰ C preferred. Only in cases where the carboxylic acids modified at the carboxyl group are not stable enough or there is a risk that racemization will occur if an optically active center is in the vicinity of the carboxyl group, it may be appropriate to use ίο, preferably at reaction temperatures below -20 ° work. In the reaction according to the invention of the carboxylic acids of the general formula V modified at the carboxyl group with the 6-aminopenicialanic acid or the compounds of the general formulas III and IV, the reactants can be reacted in equimolecular amounts. However, it can be useful to use one of the two reactants in excess in order to facilitate the purification or purification of the desired penicillin and to increase the yield. For example, 6-aminopenicillanic acid or the compounds of the general formulas III and IV can be used in an excess of 0.1 to about 0.4 molar equivalents, thereby achieving better utilization of the carboxylic acids of the general formula V. When working up the reaction mixture and isolating the penicillin, any 6-aminopenicillanic acid that may be present can easily be removed because of its good solubility in aqueous mineral acids. Any carboxylic acid present (see formula V}, on the other hand, is much more difficult to separate from the penicillin formed.

The amount of the carboxylic acids of the general formula V modified in the carboxyl group with the 6-aminopenicyanoic acid or the compounds of the general formula in the reaction according to the invention Bases added to formulas III and IV are, for example, due to the desired maintenance of a certain pH Established Where pH measurement and adjustment is not carried out or because of the lack of sufficient Amounts of water in the diluent is not possible or useful in the case of using the Compounds of the general formula III or IV about 0.5 to 2.0 molar equivalents of base, in the case of Use of 6-aminopenicillanic acid and an anhydrous reaction medium about 1.5 to 2.5 Molar equivalents of base added

The work-up of the reaction batches for the preparation of the penicillins according to the invention and their salts is carried out consistently in the manner generally known from penicillins.

The carboxylic acids of the general formula V are converted into the forms according to the invention modified at the carboxyl group by treating them with about one molar equivalent of the compounds of the general formulas VI, VII or VIII in an anhydrous, inert organic solvent in the presence of about one molar equivalent of a tertiary brings organic base, preferably triethylamine, at a temperature of about -60 ⁰ C to +30 "C, preferably -20 ° C to + 5 ° C to implement the thus formed at the carboxyl group modified forms of carboxylic acids are preferably not isolated but used together with the solvent they are in for the reaction with 6-aminopenicillanic acid or the compounds of the general formulas ΙΠ or IV Contains the reaction mixture in the reaction with aminopenicillanic acid or compounds III or IV

Water is used as a solvent for the reaction of the carboxylic acids V with the compounds VI, VII or VIII preferably water-miscible organic solvents, for example acetone, tetrahydrofuran, Dioxane, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide are used. Contains If the reaction mixture is not water, then, in addition to the solvents mentioned, there are also those such as preferably methylene chloride or chloroform is used.

The carboxylic acids of the general formula V are converted into the carboxylic acid derivatives of the general formula IX according to the invention by first adding compounds of the general formula X in an anhydrous, inert organic solvent, for example acetone, tetrahydrofuran, methylene chloride, dioxane, chloroform or dimethylformamide, in the presence of At least and preferably one molar equivalent of a tertiary base, preferably triethylamine, at temperatures of about -25 ° C to + 25 ° C, preferably -10 ° C with one mol equivalent of thionyl chloride to form one mol equivalent of base hydrochloride in an unknown intermediate, this intermediate not isolated, but these subsequently in the presence of a further molar equivalent of an organic base, preferably triethylamine, with a molar equivalent of the carboxylic acid V at a temperature of about -25 ° C to +25 ⁰ C, preferably -1O ⁰ C to +10 ⁰ C, brings to implementation. After removing the base hydrochloride by filtering off, the corresponding compound of the general formula IX can be isolated by evaporating the solvent and, if necessary, by recrystallization from inert solvents, or, if the substance is not crystalline, by briefly washing an ethereal or benzene solution, for example, with an aqueous bicarbonate solution clean at the lowest possible temperature.

The 6-aminopenicillanic acid used as a starting material in the invention was prepared according to known ones Method by cleaving penicillin-G, either obtained by fermentative processes or by chemical cleavage (see NiederL Pat No. 67/13 809). the Carboxylic acid of general formula V was derived from the amino acids of general formula XI

H ₂ N-CH-COOH

(XD

and acid halides of the general formula XII,

A - CO halogen

(ΧΠ)

where A, B and C * have the meaning given above have, as explained in more detail in the examples, prepared The acid halides XII were after Process obtained in the German patent application P17 93 2875, in the German patent no. 1,259,871, U.S. Patent Nos. 3,275,618 and 3,337,621, and Japanese application No. 12 921/64. In addition, some of the acid halides XII from the corresponding Amides by metalation with methyl lithium on the amide nitrogen and subsequent reaction with Phosgene shown

Lab Lemco 10 g Peptone 10 g NaCl 3g D (+) dextrose 10 g Buffer pH 7.4 1000 ml

The preparation of the reagents of the general formulas VI, VII, VIII and IX used is in the Literature described (cf. J. med. Chem. 9 (1966) p. 980; Ber. 96 (1963) p. 2681; Tetrahedron 17 (1962) p. 114).

The chemotherapeutic effectiveness of the new penicillins was tested in vivo and in vitro. the The in vitro inhibitory values (MIC) were determined in liquid medium in the tube serial dilution test, the reading after 24 hours of incubation

ίο took place at 37 ° C. The MIC is due to the opacity-free Tubes indicated in the dilution series. A complete medium with the following composition was used as the nutrient medium:

The spectrum of activity includes both gram-negative and gram-positive bacteria. The special one The advantage of the penicillins according to the invention is that they both in vitro and in animal experiments against Penicillin and carbenicillin resistant Klebsieila bacteria and ampicillin resistant Proteus bacteria are effective. In addition, penicillin-resistant Pseudomonas species are recorded in vitro and in vivo Killing necessary concentrations are in the serum achieved after parenteral administration

The generally excellent effect is achieved both with a single and with multiple administration. The absorption of the new penicillins takes place very quickly after subcutaneous administration, and the peak values are reached within 10 minutes. Elimination is usually just as quick. The penicillins according to the invention are acid-stable. They stay at pH = 1 microbiologically active for one hour. Some of the new penicillins are excellent tolerable, which is made particularly clear by the extremely high dose in these cases intravenous administration into the tail vein is tolerated without complications. The penicillins according to the invention can alone or formulated and administered in combination with a pharmaceutically acceptable carrier substance according to the usual pharmaceutical procedure will. For oral administration they can be in the form of tablets, which for example additionally contain starch,

so can contain lactose or certain types of clay, or in the form of capsules, drops or Granules, alone or together with the same or equivalent additives. You can also orally in the form of juices or suspensions,

ss which may contain the usual flavor corrections or colorings for such purposes.

Furthermore, the penicillins according to the invention can be administered parenterally, e.g. intramuscularly, subcutaneously or intravenously, possibly as a permanent drip sion. In the case of parenteral This is best done as a sterile solution that contains other components of the solution, such as May contain sodium chloride or glucose to make the solution isotonic. To such solutions too you can use these penicillins in the form of dry ampoules. With oral and parenteral administration, a dosage of 25,000 to 1,000,000 U / kg body weight / day is appropriate.

moderate. It can be given as a single dose or as a continuous drip infusion or divided into several Give cans. For a local treatment, the penicillins according to the invention can be used as ointments or powders prepare and use.

A superior effect of the compounds according to the invention over known acylureidopenicillins, Ampicillin and carbenicillin can be found in the following test report:

Connection off In vitro effect (MIC in Proteus mcg / ml) Sticky Animal experiments (0 = no effect, Proteus Adhesive Stqph. sieila 4 = full effect) vulg. 1017 siella 133 Coli 183/58 3400 63 CoIi 63 12.5 12.5 C 165 1 2 3 1017 DE-OS 19 29 997 6.2 12.5 2-3 example 1 DE-OS 19 04 851 200 100 1 1 4th Example 14a DE-OS 19 29 997 100 50 3 Example 2 DE-OS 19 04 851 > 400 200 0 0 4th Example 14d 50 400 4th 0 3 Ampicillin 200 > 400 Λ Carbenicillin 12.5 12th 3 According to the invention 50 50 4th 2-3 3-4 example 6.2 25th 3-4 3 4th 1 50 4-20 50 20-100 1-2 3-4 3-4 4th 2 3.1 12.5 20-100 2-3 4th 2-3 4th 3 4-20 25th 4-20 50 3-4 4th 2 1-2 4th 25th 20-100 400 4th 4th 2-3 (+) 0 5 6.2 6.2 25th 100 2 4th 3 0 6th 6.2 25th 12.5 25th 2 3-4 2-3 2 7th 1.6 0.8-4 6.2 4-20 2-3 1-2 4th 4th 8th 6.2 20-100 12.5 20-100 2-3 4th 3 2-3 9 0.8-4 4-20 3-4 10 ~ 4 4-20 2-3

The following examples illustrate the invention.

The O-lactam content of the penicillins was determined iodometrically. All substances described here showed an IR spectrum corresponding to their constitution. The NMR spectra of the penicillins were recorded in CD ₃ OD-LoSMIg; the signals given in the examples correspond to the r-scale; they agree with the respective constitution.

The figures given for the effectiveness against certain bacteria (EImX) are minimal hernia concentration in the tube serial dilution test after incubation for 24 hours.

When specifying: "Effectiveness in animal experiments", "A" means that the penicillin in question is on the Mouse with subcutaneous application against Proteus vulgaris 1017 more effective than ampicillin and "B" that it against Klebsieila aerobacter 63 is more effective than ampicillin and carbenicillin

When calculating the analysis values, the water content of the penicillins was taken into account

example 1

D-a- (3-Acetyl-3-allylureido) benzylpenicillin sodium

5.5 parts by weight of D - "- (3-acetyl-3-tlryl-ureido) -" - phenylacetic acid were dissolved in the absence of moisture 50 parts by volume of dichloromethane and added 2.0 parts by weight of triethylamine with cooling. It was then ^{cooled to -5 C} to -10 ° C and 3.6 parts by weight of tetramethyl chloroformamidinium chloride added in a few portions over the course of a few minutes. The mixture was then stirred for 30 minutes at this temperature, and any undissolved material was suctioned off without the solution heating up above 0 ^° C. The filtrate was cooled to -10 ° C and

it fugte at once to -10 ⁰ C cold solution of 4.1 parts by weight of 6-aminopenicillanic acid and 3.4 parts by weight of triethylamine in 50 parts by volume of dichloromethane. [The aminopenicillanic acid was with the triethylamine and 2 parts by weight of a ground molecular sieve (Zeolite VS 10-2) stirred for 1.5 hours at room temperature; then you sucked moisture conclusion and sat the filtrate for reaction.] The combined solutions was allowed one hour at 0 ⁰ C are then poured in 100 parts by volume of water a. The pH was adjusted to 6.5 Separated dichloromethane phase and the aqueous phase with 200 parts by volume of a 1: 1 mixture of ethyl acetate and ether covered with vigorous stirring and ice-cooling, mixed with enough 2 η hydrochloric acid, in order to set a pH of 2.0 in the aqueous layer. The organic phase was separated, washed with 2 χ 40 vol parts of water and dried over MgSO ^ for two hours in the refrigerator

now mixed with 20 parts by volume of a 1 M solution of sodium 2-ethylhexanoate in methanol-ether, the mixture was concentrated largely in vacuo at 0 ⁰ C, took methanol in just sufficient quantity and precipitated as the sodium salt of penicillin by adding excess ether while shaking vigorously.

Yield: 67%.

0-lactam content: 81%.

Calculated: C 51.4, H 5.3, N 10.9, S 6.2; Found: C 51.5, H 6.0, N 10.3, S 5.5.

According to the IR spectrum and thin-layer chromatogram, the product was identical to one made from ampicillin and N-acetyl-N-allylcarbamic acid chloride. provided comparator product

Example 2

D - «- (3-y-chlorobutyryl-3-methylureido) -benzylpenicillin-sodium

As described in Example 1, a solution was prepared from 6.25 parts by weight of D - «- (3-y-chlorobutyryl-3-methylureido) -phenylacetic acid and 3.6 parts by weight of tetramethylchloroformamidinium chloride which had 1.5 Hours at -5 ° to -10 ⁰ C was held. It was then combined with a solution of 4.1 parts by weight of 6-aminopenicillanic acid and 3.4 parts by weight of triethylamine in dichloromethane, which solution was kept at room temperature for one hour. It was then worked up as described in Example 1.

Yield: 62%.

j3-lactam content: 84%.

Calculated: C 48.0, H 5.1, Cl 6.4, N 10.2, S 5.8; Found: C 48.1, H 5.2, Cl 5.8, N 9.9, S 6.4.

NMR signals at τ =

2.3-23 (5H) ₁ 4.45 (1H), 4.55 (2H),

5.8 (1H), 6.4 (2H), 6.75 (3H), 73 (2H),

7.9 (2 H) and 8.5 ppm (6 H).

Chlorobutyryl-3-methyl-ureido) - (2-thienyl) -acetic acid, 3.5 parts by weight of tetramethylchloroformamidinium chloride and 4.06 parts by weight of 6-aminopenicillanic acid manufactured.

Yield: 64%.

0-lactam content: 95.5%.

NMR signalsbeir = 2.5-3.2 (3H), 4.1 (IH), 4.4 (2H),

5.8 (1H), 6.3 (2H), 6.7 (3H), 7.2 (2H),

7.9 (2 H) and 8.4 ppm (6 H).

Effectiveness in animal experiments: B. Example 5

A. D - «- (3-Isopropoxycarbonyl-3-methylureido) phenylacetic acid

Example 3

D, L - «- (3-Benzoyl-3-methyl-ureido) -p-methylbenzylpenicillin sodium

As described in Examples 1 and 2, this penicillin was made from 53 parts by weight of D, L-Ä- (3-benzoyl-3-methylureido) -p-tolyl-acetic acid, 3 parts by weight of tetramethylchlorformamidium chloride and 435 parts by weight Parts made of 6-aminopenicillanic acid

Yield: 59%.

0-lactam content: 84%.

Calculated: C 54.5, H 53, N 9.7, S 7.9; Found: C 543, H 5.9, N 9.5, S (5.6).

NMR signals at τ =

2 ^ (5 H), 2 ^ -3.0 (4 H), 43-4.65 (3.0 H), 5.8 (1 H), 63 (3 HX 7.7 (3 H) and 8.2-8.5 ppm (6H).

Effectiveness in animal experiments: A and B. Example 4

D, L- ^ 3 -) »- CUorbutyryl-3-ynethyl-iireido) - (2-thienyl) -methyl-penicillin-sodium

This penicillin was in the manner described in Examples 1 and 2 from 53 parts by weight of D, L- (3-y- 15.1 parts by weight of D (-) - C-phenylglycine were through Add sufficiently dilute caustic soda in 250 Parts by volume of 50% strength aqueous dioxane dissolved. The pH was then reset to 7.8 with 2η HCl, some of the phenylglycine precipitating in finely divided form. The mixture was cooled to ⁰ ° C. and left 18.0 parts by weight of N-isopropoxycarbonyl-N-methylcarbamine acid chloride in 30 parts by volume of anhydrous dioxane im Add dropwise over the course of 30 minutes, the pH value 7.5-8.0 being maintained by the simultaneous addition of 2 η sodium hydroxide solution. One then stirred in Room temperature until no alkali is added pH maintenance was more necessary. so 300 parts by volume of water were added and the solution extracted 1 with 150 parts by volume of ether it was acidified with 2 η HCl to pH = 2 and the precipitated oil was taken up in several portions of ethyl acetate.

The combined organic solutions were washed once with 100 parts by volume of water and _{dried over MgSO 4 for a} few hours. After filtration, the mixture was evaporated and the oily residue was freed from dioxane at 60-80 ° C. and 0.1 torr. The glassy product fell into 48% yield. It was according to the NMR spectrum and the thin-layer chromatogram completely pure.

Calculated: C 57.1, H 6.1, N 9.5; found: C 56.9, H 5.7, N 9.8.

NMR signalsbeir =

-03 (1H), +0.4 (1H), 23-23 (5H), 4.6 (1 H), 5.0 (1 H), 63 (3 H) and 8.75 ppm (6 H).

B. D - «- (3-Isopropoxycarbonyl-3-methylureido) -benzyl-penicillin-sodium

This penicillin was prepared in an analogous manner from 53 parts by weight of D - «- (3-isopropoxyearbonyl-3-nieihyi-ureido) phenylacetic acid, 3.7 parts by weight of tetramethylchloroformamidinium chloride and 4 /) parts by weight of 6-ami nopenicillanic acid produced.

Yield: 45%.

0-lactam content: 86%.

Calculated: C 48.8, H 5.6, N 10.4, S 53; Found: C 48.7, H 53, N 10.8, S 5.8.

NMR signals at τ = 23-23 (5H), 4.4 (1H), 4.55 (2H), 5.0 (1H), 5.8 (1H), 6.85 (3H), £ 8 (6H), and 8.7 ppm (6 H).

The following table Effect of this product.

shows the bacteria

Bacterial species

Effectiveness [U / ml]

The following table shows the biological effectiveness of this penicillin.

Minimum inhibitory concentration in U / ml:

Eschenchia coli 14 6.25 Escherichia coli C 165 50 Eschenchia coli 183/58 124 Pseudomonas aer. Bonn. 50 Pseudomonas aer. Walter 100 Example 6

D-oc- (3-n-Butoxycarbonyl-3-methyIureido) -benzylpenicillin-sodium

10

15th

This penicillin was prepared in an analogous manner from 5.6 parts by weight of D - «- (3-n-butoxycarbonyl-3-methyIureido) phenylacetic acid, 33 parts by weight of tetramethylchloroformamidinium chloride and 3.6 parts by weight of 6-aminopenicillanic acid The ureidoacetic acid was stirred with the tetramethylchloroformamidinium chloride at -5 ° C in acetone for only 20 minutes Yield: 38%.

jS-Lact & m content: 61%.

Calculated: C 48.1, H 6.0, N 9.7, S 5.6;

found: C 48.4, H 5.5, N 9.4, S 5.5.

NMR signalsbeir = 23-2.8 (5H), 4.45 (1H) 4.55 (2H), 5.8 (3 H), 6.85 (3 H) and 8.1 -83 ppm (13 H).

E. coli 14 3.12 E. coli A 261 400 E. coli C 165 6.25 E. coü 183/58 3.12 Proteus 3400 12.5 Proteus 1017 12 ^ Pseudomonas aerug. Bonn 25th Pseudomonas aerug. Walter 50 Klebsieila K 10 200 Klebsiella 63 100 Staphylococcus aureus 1777 E. 200 Staphylococcus aureus 133 <0.7 Enterococcus ATCC 9790 100 Example 8

Example 7

D-ec-ß-Cyclohexyloxycarbonyl-S-methyl-ureido) -benzylpenicillin-sodium

There were 4.5 parts by weight of 6-aminopenicillanic acid in 60 parts by volume of 50% aqueous tetrahydrofuran suspended, the amount of triethylamine just necessary to dissolve the aminopenicillanic acid is added, the solution obtained, which had a pH of 8.0 (glass electrode) cooled to 0 ° C., the solution of 8.0 Parts by weight of O-fD-a-ß-Cyclohexyloxycarbonyl-S-me-

thylureido) phenylacetyl] -C-cyano-C-ethoxycarbonyl-formaldehyde oxime in 25 parts by volume of tetrahydrofuran was added dropwise and the pH of the solution was kept at 7.5 by adding triethylamine accordingly . -Parts of water are added, the solution is adjusted to pH 64, the tetrahydrofuran is largely removed in vacuo in a rotary evaporator, the remaining aqueous solution is covered with a 1: 1 mixture of ether and ethyl acetate, stirred and cooled to 0 to 5 ° C and acidified to pH 1.5 using 2 η hydrochloric acid

The organic phase was then separated off, washed with water, over sodium sulfate in a refrigerator dried and the sodium salt of penicillin using a 1 M solution of sodium 2-ethylhexanoate in methanol-containing ether precipitated. The supernatant solution was from the initially oily precipitation poured off and converted into a colorless powder by rubbing with dry ether. j3-lactam content: 82%.

NMR signalsbeir = 2.4-3.0 (5H), 4.3-4.7 (3H), 5.2 (IH), 5.8 (1 H), 6.8 (3 H) and 7.9-9.0 ppm (16 H).

D-a- (3-Auyloxycarbonyl-3-methylureido) -benzylpenicillin-sodium

There were 7.1 parts by weight of 6-aminopenicillanic acid in the mixture of 120 parts by volume of methylene chloride and 10 parts by volume of triethylamine dissolved, 12.4 parts by weight of O-iD-α-β-allyloxycarbonyl-S-methylureidoJ-phenylacetyl] -C-cyano-C-ethoxycarbonyl-formaldehydroxime added, the solution left to stand in the refrigerator for 24 hours, with 150 parts by volume of methylene chloride diluted, extracted exhaustively with saturated sodium bicarbonate solution, the combined bicarbonate extracts with a 1: 1 mixture of ether and Covered with ethyl acetate, while stirring with 2 η hydrochloric acid, the pH in the aqueous phase to 5.0 set, the organic phase separated off, the aqueous phase with fresh ether-ethyl acetate mixture covered, while stirring and cooling with ice, the aqueous phase then up to pH 1.5 with 2 η hydrochloric acid acidified, the organic phase separated and the sodium salt des in the manner described in Example 7 Penicillins like and isolated

Yield: 30%.

0-lactam content: 74%.

Calculated: C 49.7, H 5.2, N 10.5, S 6.1; Found: C 49.9, H 6.1, N 10.4, S 5.6.

NMR signals

2.4-2.8 (5H), 3.7-43 (1H), 4.4-4.9 (5H), 5.1-5.4 (2H), 5.8 (1H), 6.8 (3H) and 8.45 ppm (6H). ·

Shows the biological effectiveness of this penicillin the table below.

Minimum inhibitory concentration in U / ml:

E. coli 14 E. coli A 261

0.8-4 100-500

230 241/11

Minimal inhibition concept in U / ml:

E. coli C 165 E. coli 183/58 Proteus 3400 Proteus 1017

Pseudomonas aerug. Bonn Pseudomonas aerug. Walter Klebsiella K 10 Kiebsiella 63

Staphylococcus aureus 133 Enterococcus ATCC 9790

4-20

4-20

20-100

20-100

4-20

20-100

20-100

20-100

0.8-4

20-100

Example 9

D- <x- {3- (2-Ther.oyl) -3-methylureido] benzylpenicillin sodium

To produce this penicillin, 3.9 parts by weight of - «- [3- (2-Thenoyl) -3-methyliireido} -phenylacetic acid were dissolved in 55 parts by volume of acetone with the addition of 2.0 parts by volume of triethylamine, at - 5 ° to - 10 ⁰ C 23 parts by weight of 1-methyl-2-chIorpyrroliniumchlorid added, stirred for 45 minutes at the same temperature, a solution of 3.1 parts by weight of 6-aminopenicillanic acid in the mixture of 60 parts by volume of 90 % aqueous acetone and triethylamine, which had a pH of 7.5, was added, the mixture stirred for 2 hours at -5 ⁰ C and worked up for the isolation of the sodium salt of penicillin

Yield: 56%.

/ 3-lactam content: 64%.

NMR signals

2.1 -3.0 (8 HX4 ^ 5-4.8 (3 H), 5.8 (1 H), 6.55 (3 H) and 8.45 ppm (6 H).

Example 10

D-A- [3- (3,5-Dimethylisoxazoloyl-4) -3-methylureido] benzylpenicillin sodium

To produce this penicillin, 33 parts by weight of D - «- [3- (3 ^ -Dimethylisoxazoloyl-4) -3-methylureido] phenylacetic acid were dissolved in 60 parts by volume of methylene chloride with the addition of 2.0 parts by volume of triethylamine, the solution to - cooled to -10 ⁰ C, 2 £ parts by weight

ίο 1-methyl-2-chloropyrromic chloride added, the mixture allowed to stand at -10 to -35 ° C for 90 minutes (Solution A).

On the other hand, 3.1 parts by weight of 6-aminopenicillanic acid were suspended in 60 parts by volume of methylene chloride, 3.4 parts by volume of triethylamine were added and the mixture was stirred at 22 ° C. for 4 hours (solution B). Then became Solution B cooled to 0 to -5 ° C and solution A in the course of 30 minutes with stirring and further Cooling added in several portions.

The mixture was then stirred for a further 1 hour at 0 to 5 ° C. , the solvent was stripped off in vacuo, the residue was taken up in water and a 1: 1 mixture of ether and ethyl acetate, the pH was adjusted to 7.5 with stirring, and the organic phase separated, the aqueous phase covered with a fresh ether-ethyl acetate mixture, with stirring and Cooling with ice, the pH was brought to 1.5 by means of 2 η hydrochloric acid, and the organic phase was separated off with water washed, over magnesium sulfate for 2 hours im Dried in the refrigerator, and the penicillin isolated as the sodium salt Yield: 50%. 0-lactam content: 80%.

Calculated: C 50.7, H 5.0, N 12.3, S 5.6; Found: C 51.1, H 5.4, N 11.6, S 5.8.

NMR signalsbeir =

235-2.9 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.8 (3 H), 7.6 (3 H), 7.75 (3 H) and 8.45 ppm (6H).

Claims (3)

L penicillins of the general formula I. A-CO-NH-CH-CO-NH-B Patent claims: -N CH ₃ COOH in the B phenyl and A — CO — NH- a (3-acetyl-3-allylureido) - or (S-y-chlorobutyryl-B-methylureido) - or (3-isopropoxycarbonyl-3-methylureido) - or (3-Cyclonexyloxycarbonyl-3-methylureido) - or ß-allyloxycarbonyl-S-methylureido) - or [3- (2-ThenoyI) -3-methylureidol or [3- (3,5-Dimethylisoxazoioy] -4) -3-methyhireido -] - or (3-n-butoxycarbonyl-3-methylureido} group or B p-methylphenyl and A-CO-NH- a (3-benzoyl-3-methylureido) group or B 2-thienyl and A-CO-NH- a (3-y-chlorobutyryl-3-methylureido) group represent and with respect to the chiral center C * one of the two possible Diastereomers with the R or S configuration can be or can be present as mixtures of these two diastereomers, as well as their non-toxic, pharmaceutically acceptable salts. 2. Medicament containing at least one compound according to claim 1. 3. Process for the preparation of compounds according to claim 1, characterized in that one 6-aminopenicillanic acid (formula II) or compounds of the general formulas IH or IV H ₂ N-CH-CH -N CH ₃ COOH CH ₃ ÖD H ₂ N-CH-CH C N O CH CH ₃ CH ₃ R ₇ CO-O-Si-R ₈
R ₉ R ₇ R ₈ - Si - NH - CH - CH CH ₃ CH R ₇ CO-O-Si-R ₈ \
R ₉ (ΠΙ) (IV) wherein R ₇ , R ₈ and R _{9 are} alkyl with up to 6 carbon atoms in a manner known per se with on the carb Oxyl group activated carboxylic acids of the general formula V A —CO — NH — CH — COOH (V)
B. wherein A — CO-NH -, B and C * have those in claim 1 have given meaning, in the case of the use of 6-aminopenicillanic acid in anhydrous or aqueous solvents in the presence of a base, in the case of using the compounds of the general formulas III or IV in anhydrous and hydroxyl-free solvents with or without the addition of a base at a temperature in the range from about -20 ° to +50 "C brings to implementation