DE2152968A1 - NEW PENICILLIN - Google Patents

Description

FARBENFABRIKEN BAYER AG

LEVERKCJSEN-Bayerwetk ^ * · Qf (J ^ JQ7J

Zeutralbereidi Si / Wo
Patents, trademarks and licensers, α

Type Ib Pha

New penicillins

The present invention relates to new penicillins, several processes for their preparation and their use as
Medicinal products in human medicine, as therapeutic agents in poultry and mammals, additives and as
growth promoting agents in animals.

The new synthetic compounds are useful as therapeutic agents in poultry and mammals, as well as in humans, in the treatment of Gram-positive and Gram-negative bacteria, and in particular bacteria in the group
the enterobacteria and pseudomonads caused infectious diseases. They can be used orally and parenterally.

Antibacterial agents such as ampicillin (U.S. Patent
2,985,648) have proven themselves in the treatment of infections by Gram-positive and Gram-negative bacteria as very

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proven effective. However, they are not capable of infections caused, for example, by bacteria of the Klebsiella group Aerobacter or caused by indole-positive Proteus strains will fight.

Carbenicillin (U.S. Patents 3,142,673 and 3,282,926) is found in humans in infections by Klebsiella Aerobacter only effective when given in sustained high doses that can only be obtained by infusion.

The present invention relates to methylpenicillins which are substituted in the methyl group by a radical B and an acyl-bi ~ ureido radical whose carbonyl function in the acyl group can be replaced by an -SO ₂ group:

Acyl-NCNCN- (= E is: = 0, = S, = N- $ P m <^

6- (oc-Biureido) -acetamido-penicillanic acids are in the U.S. Patent 3,483,188 and German Offenlegungsschrift No. 1 959 920, but all have in 6- (oc-Biureido) -acetamido-penicillanic acids described and claimed in these patents no acyl radical on the nitrogen atom in the 5-position des Biureidorestes.

The present invention relates to compounds of the general formula I:

AZ-NH-CH-CO-NH-CH-CH ^ X ^^ _If

OOH

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where A is a group

^X N- NHC-NYN-

-Q ₁ - / ^R 2 ^R 3

R ₁ -XN ^ ^ N-

Rl -C NYN- R ₁ -XN CN-

N ^^ Q, R ₃ h + ^ Ji R ₃

R ₁ -XNC N- X NYN-

Vy R ₃

NCXNYN R ₂ Nx ^ Q ₁ VQy R

R -QNYN-Π J

represents

X is a group -S- or -C- or -G-,

S S F

Y is a group -C-, -C-, -C-,

NR N-aryl N-SO ₂ -R N-SO ₂ -aryl

-C-, -C-, -C- or -ί-

Z is a group -C- or -C-, Q _{1 is} a group

? 5

3 »- (JI-CO-Cp,

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0 or

Q ₈ a group

G GGGG G

G GGGRG G

GGGG GGG

RG GO G G

G / "" Χ G G ^ = V G

⁰ Po or 1 9 " ^{f <} tf ⁽ 9

G GGG

represents

wherein R is a straight-chain or branched alkyl radical with up to 5 carbon atoms

R ₁ ^ alkyl with "up to 10 carbon atoms, cycloalkyl with up to 10 carbon atoms, alkenyl with up to 10 carbon atoms and cycloalkenyl with up to 10 carbon atoms, vinyl, arylvinyl, mono-, di- and trihalo-lower alkyl, H ₈ N-, R -NH-, (R) ₂ ^ N-, Aryl-NH-, Aryl lower alkylamino, Alkoxy * 'with up to 8 carbon atoms, Aralkoxy ⁺ ' with up to 8 carbon atoms, Cycloalkoxy ⁺ 'with up to 7 carbon atoms ,. Aryloxy ⁺ % a group ROV-, RSV-, N = CV-, RO-CO-V-, H ₈ N-CO-V-, R-NH-CO-V->

means,

only if X _{2 is not -SO 2} - at the same time.

3rd A..14 Q38 - 5th

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V is a bivalent organic radical with 1 to 3 carbon atoms,

η is an integer from 0 up to and including 2,

Sa. and R ^ each hydrogen, alkyl and alkenyl with each up to 8 carbon atoms, vinyl, allyl, propenyl, cycloalkyl and cycloalkenyl with up to 6 carbon atoms each, Is mono-, di- and trihalo-lower alkyl or aryl,

PR ₄ , R ₅ and R _{6 are} each hydrogen, nitro, nitrile, (R) ^> N-, (R) ^ = N-CO-, R-CO-NH-, RO-CO-, R-CO-O -, R-, RO-, H _a N-SO ₂ -, chlorine, bromine, iodine, fluorine or trifluoromethyl,
and

£ hydrogen or R means, the arrow in the divalent intermediate piece V ~ J is intended to express that the

The connection of two atoms caused by the two free valences of this intermediate piece is not arbitrary, softderain in the manner indicated by the arrow should take place,

j | a group of the formula

038 - 6 -

309-17 / 7 *

, R ₆ land R ^ hydrogen, halogen, R-, RO-, RS-, R-SO-, R-SO ₂ -, nitro, (R) -P = N-, R-CO-NH-, HO, R-CO-O- denotes, where R has the meaning given above and its non-toxic, pharmaceutically acceptable salts.

The penicillins of the general formula I and their non-toxic, pharmaceutically acceptable salts can with respect to the chiral center C_f in the two possible R and S configurations and as mixtures of the resulting diastereomers.

According to the invention, methods for producing the Penicillins of the formula created by using 6-aminopenicillanic acid (formula II) or compounds of general formulas III or IV

H ₂ N-CH-CH> r ^ ^H 3 ^Ιτ

-CH ^
COOH

H ₂ N-CH-ClT ³ \ _{C <} CH ₃

N-CH-ClT ³ \ _C

CO-O-Si ^ -R ₁ , ^ R ₁₂

R ₁₁ - ^ Si-NH-CH-CH> ^ " ³ IV ¹² J ^ --N \ /

CO-O-Si-R _1. ,

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where R ₁₀ , R ₁₁ and R ₁₂ each denote alkyl with up to 6 carbon atoms, with carboxylic acids of the general formula V which have been specially modified on the carboxyl group (see below for explanations)

■ K
AZ-NH-CH-COOH V,

wherein A, Z, B and C have the meanings given above, in the case of the use of 6-aminopenicillanic acid in anhydrous or water-containing solvents in the presence of a base, in the case of the use of the compounds of the general formulas III or IV in anhydrous and hydroxyl-free solvents without or involves the addition of a base at a temperature in the range of about -70 ⁰ C to +50 ⁰ C, preferably at -50 ⁰ C to 0 ⁰ C for reaction.

If the reaction of 6-aminopenicillanic acid with the carboxylic acids V changed in the carboxyl group, this reaction can be carried out in aqueous solvents in a pH range of about 2-9, preferably at pH 2-3 or 6.5-8 , 5 are executed . When converting the carboxylic acids V into the carboxylic acids V with modified carboxyl groups, the salts of the general formula Va or the silyl esters of the general formulas Vb or Vc can also be used

A-Z-NH-CH-COO ^] Me Va

A-Z-NH-CH-COO-SI ^ r! ι vb

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A-Z-NH-CH-COO

B ^ Si <r £ ¹ ° Vc

A-Z-NH-CH-COO

I B

in which A, Z, B, R ₁₀ , R ₁₁ , R ₁₉ and C have the meaning given above and Me ¹¹ ^ ⁺ 'stands for a cation of the alkali or alkaline earth metals, or for a cation of the element aluminum and η is in each case an integer is from 1 to 3, use as starting compounds.

You can use the carboxylic acids of the general formula V, or convert their salts Va or their silyl esters Vb or Vc into the carboxylic acids V with the carboxyl group changed, that they with about one molar equivalent of the compounds of the general formulas VI, VII, VIII or IX

13th

VI

w-

VII

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H ₂

CH ₂ jC-W

VIII

W '

IX

where R has the meaning given above, R ₁₃ either has the same meaning as R or phenyl, R _{14 is} a divalent organic radical - (CH ₂ ) ₄ -, - (CHg) ₅ - or - (CH ₂ ) ₂ -0 - (CH ₂ ) ₂ - and 'W is halogen, in the case of using the compounds V or Va in a water-containing or anhydrous organic solvent, in the case of the use of the compounds Vb or Vc in an anhydrous and hydroxyl-free, inert organic solvent, in the presence or absence of a base at -70 ⁹ C to +30 ⁰ C, preferably at -50 ⁰ C to ^{0 0} C to implement. Here and for the subsequent reaction with the compounds of the general formulas II, III or IV, it can be advantageous if this reaction is carried out in the presence of about one molar equivalent of the N-hydroxy compounds of the general or specific formulas X, Xa or Xb:

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- 10 -

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2152988

HO-N = C <

I CO-CH ₂

Il N

OH

in which U is the radical -C = N and / or -COO lower alkyl, can run off.

On the other hand, the carboxylic acids of the general formula V, their salts Va or their silyl esters Vb or Vc can thereby be used into the carboxylic acids V changed at the carboxyl group, so that they can be mixed with about one molar equivalent of the compounds of the general formulas XI or XIa, or half a to one molar equivalent of the compounds of the general Formulas XII or XIIa:

_x ^ ₁₃

W-CH = NO ₃ XI> C = Nv XII

W-CH = NR ₁₄ XIa ^ C = NR ₁₄ XIIa

/ ν / 'V

in which W, R ₁₃ and R _{14 have} the meaning given above, in the presence of one molar equivalent (based on the carbon Ie A 14 038-11 ~

^: 098 1 11 1 1 IU

acids of the general formula V) of the N-hydroxy compounds X, Xa or Xb, in the case of the use of the compounds V or Va in an aqueous or anhydrous organic solvent, in the case of the use of the compounds Vb or Vc in an anhydrous and hytiroxylgruppenfreii / indifferent organic solvent, in the presence or in the absence of a base at -70 ⁰ C to +30 ⁰ C _s preferably at -50 ⁰ C to 0 ⁰ C to implement.
In the event that the chiral center C has optical activity

^ is present, one can see a possible racemization at this Prevent this by taking the transfer the carboxylic acids V, or their salts Va, or their silyl esters Vb or Vc into the carboxylic acids modified at the carboxyl group V no or relatively weak organic bases, for example N-M & hylmorpholine, N-ethylmorpholine, N, N ~ dimethylaniline, Pyridine or inorganic bases or buffer mixtures are used. You can also use the carboxylic acids of the general Formula V is converted into carboxylic acids with modified carboxyl groups by compounds of the general

W Formula X:

HO-N = CsT X U

wherein U has the meaning given above, in an anhydrous, inert organic solvent in the presence of at least one molar equivalent of an organic base, which serves as an acid scavenger, at temperatures from about -40 ° C to +25 ⁰ C with one molar equivalent of thionyl chloride to form one molar equivalent of base hydrochloride in not

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known intermediate compounds and these without isolation in the presence of a further molar equivalent of a base with one molar equivalent of the carboxylic acids of the general formula V or one molar equivalent of the compounds of the general formulas Va, Vb or Vc, either no base or up to one molar equivalent of a base being added , at a temperature of about -4O ⁰ C to +30 ⁰ C to implement. The carboxylic acids (V) of the general formula XIII changed at the carboxyl group are obtained:

A-Z-NH-CH-Cf /

I X) -N = CC XIII

Here, A, Z, B, C and U have the meanings given above.

In addition, the carboxylic acids of the general formula V can thereby be converted into carboxylic acids with modified carboxyl groups of the general formula XIII convert them in the presence of about one molar equivalent of the compounds of the general formula X with about one molar equivalent of a carbodiimide in a diluent - in the case of subsequent use of the compounds of the general formulas III and IV in an anhydrous and hydroxyl group-free Diluent - brings about implementation. In the implementation of 6-aminopenicillanic acid according to the invention with the carboxylic acids V modified at the carboxyl group, the 6-aminopenicillanic acid is preferably used as a solution their salt is used with an acid or a base. A suitable solvent for this is, for example, water

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or mixtures of water and water-miscible organic solvents such as tetrahydrofuran, dioxane, acetonitrile, Isopropanol, acetone, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric acid triamide. Suitable acids are for example hydrochloric acid, sulfuric acid and phosphoric acid. To convert the 6-aminopenicillanic acid into one of the To convert the above-mentioned solvent dissolved salt of a base, can be used as suitable bases, for example inorganic bases such as sodium carbonate, sodium hydroxide, sodium bicarbonate, the corresponding potassium and calcium additives * bonds, calcium oxide, magnesium oxide, magnesium carbonate or Buffer mixtures, as well as organic bases such as N-methylmorpholine, N-ethylpiperidine, Ν, Ν-dimethylaniline, pyridine, triethylamine use. A particularly suitable solvent is a solution of 6-aminopenicillanic acid in an anhydrous medium Chloroform or dichloromethane and for salt formation as base, for example, triethylamine, diethylamine, N-ethylpiperidine, N-ethylmorpholine and pyridine. The salts of 6-aminopenicillanic acid must in the reaction according to the invention with the carboxylic acids changed at the carboxyl group V cannot be completely resolved. Some of them can also be in the form of a suspension. Preferably suitable solvents for the reaction between the silyl compounds of 6-aminopenicillanic acid of the general formulas III or IV and the at the Carboxyl group-modified carboxylic acids V are those which have silanyl radicals attached to nitrogen and oxygen are indifferent. These preferably include all the organic solvents that do not contain any N-H and 0-H groups

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contain, for example tetrahydrofuran, dioxane, diethyl ether, Acetonitrile, benzene, carbon tetrachloride, chloroform, dichloromethane, dimethylformamide or acetone, if at this Reaction according to the invention between the silyl derivatives III or IV of 6-aminopenicillanic acid and those on the carboxyl group modified carboxylic acids V bases are added - «Uasex» it is preferably those that do not contain any N-H and O-H C groups contain.

In general, the reaction according to the invention between the carboxylic acids V and modified at the carboxyl group of 6-aminopenicillanic acid or its silicon compounds III or IV carried out so that equimolecular amounts of the reactants are used. However, it can be expedient be to use one of the two reactants in excess in order to purify or purify the desired To facilitate penicillins and increase the yield. For example, 6-aminopenicillanic acid can be used or the compounds of the general formulas III or IV with an excess of 0.1 to about 0.4 molar equivalent use and thereby a better utilization of the modified carboxylic acids of the general carboxyl group Reach Formula Vee. When working up the reaction mixture and isolating the penicillin, it may be possible 6-aminopenicillanic acid present because of its good solubility Easily removed in aqueous mineral acids. Any carboxylic acid present (see formula V) can, however, be used more difficult to separate from the penicillin formed.

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The amount of the BassDlet added in the inventive reaction of the carboxylic acids of the general formula V modified at the carboxyl group with 6-aminopenicillanic acid or the compounds of the a i Jg ^ ine inen formulas ITI and IV at -. <■ ■ .pie.lswe.ise determined by the desired maintenance of a bestinnra'sii pH where a pH ~ Messuii £ ηηά setting is Jiiv-iit or of the fact before) sufficient amounts of water. in the diluent is not possible or appropriate, will hv , Fa] Ie of "using the compounds eier all ^ emein-zi

_k formula JIj or IV, if a base is set at all, up to about 2.0 molar equivalents of base, if 6-aline inopenicillanic acid and an anhydrous reaction medium are used, about 1.5 to 2.5 molar equivalents of base are added, The amount of acid added in this reaction according to the invention is also determined, for example, by the desired maintenance of a certain pH or pH range. In general, it is advantageous to carry out the reaction according to the invention between the carboxylic acids V modified at the carboxyl group and the 6-aminopenicillanic acid or their SiIy 1-

w derivatives III or IV should be carried out at the lowest possible temperatures. As a result, purer products can be obtained, the yields can be improved and an optical activity present at the chiral center C * can be protected from racemization. However, not only the possibly insufficient solubility of the reactants at lower temperatures or a possible beginning crystallization of the solvent sets limits here. On the other hand, by excessively reduced reaction temperatures, the reaction

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speed may be reduced so much that yield reductions may even occur. The ones in the examples specified temperatures can, as with most chemical reactions, undercut but also exceeded. However, if you go considerably beyond the ones specified there Beyond these values, side reactions are to be expected, which reduce the yield and are detrimental to the purity of the products influence. In the preparation according to the invention of the carboxylic acids V modified at the carboxyl group from the Carboxylic acids V or their salts Va and the compounds of the general formulas VI, VII, VIII or IX are preferred anhydrous, inert solvents or mixtures of these solvents such as tetrahydrofuran, dioxane, dichloromethane, Chloroform. Ether, benzene, acetone, acetonitrile, dimethylformamide or hexamethylphosphoric triamide are used. However, not too large amounts of water or of alcohols such as isopropanol or tert-butanol can be present. However, if this reaction according to the invention is based on the silyl compounds Vb and Vc, only organic solvents that do not contain any N-H or O-H groups, e.g. dichloromethane, Chloroform, tetrahydrofuran, dioxane, diethyl ether, acetonitrile, benzene, acetone or dimethylformamide.

If in the reaction according to the invention between the carboxylic acids V, their salts Va or their silyl compounds Vb or Vc with the compounds of the general formulas VI, VII, VIII or IX bases are added, so are practical for this all bases are suitable, provided they are opposite to acylating agents

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are sufficiently indifferent and if they, in the case of Use of SiIy! Compounds Vb or Vc, no 0-H groups, preferably do not contain any O-H and N-H groups.

The reactants in the reaction according to the invention between the carboxylic acids of the general formula V, their Salts Va or their silyl compounds Vb or Vc and the compounds of the general formulas VI, VII, VIII or IX are preferably reacted with one another in equimolecular amounts. However, it can have a beneficial influence on the purity of the products or the yield if one of the two reactants used in more or less large excess.

When converting the carboxylic acids of the general formula V into the forms modified at the carboxyl group, it is then expedient to work at the lowest possible temperatures if an optical activity present at the chiral center C is to be preserved from racemization. Temperatures of about-40 ° C to -7O ⁰ C are preferred. For the same reasons, it is advantageous to keep the reaction time for the conversion of the carboxylic acids of the general formula V into the forms changed at the carboxyl group as short as possible. It can be useful to adhere to conversion times of about a minute or a few minutes. The inventive reaction of the carboxylic acids of the general formula V, their salts Va or their silyl compounds Vb or Vc with the compounds of the general formulas VI, VII, VIII or IX in the presence of the N-hydroxy compounds X, Xa or Xb

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and the inventive implementation of the compounds V, Va, Vb or Vc with the compounds of the general formulas Xl, XIa, XII or XIIa, which only in the presence of the N-hydroxy compounds X, Xa or Xb is carried out can be carried out in exactly the same way as the previously explained reaction of the carboxylic acids V, their Salts Va or their silicon derivatives Vb or Vc seil: the compounds VI, VII, VIII or IX, only that about one molar equivalent of said N-hydroxy compounds per mol. the compounds V, Va, Vb or Vc is added.

In the preparation according to the invention of the modified carboxylic acids V of the general formula XIII, one starts from the compounds of the general formula X, which are present in solvents such as acetone, tetrahydrofuran, dioxane, dichloromethane, chloroform, benzene, ethyl acetate, diethyl ether or dimethylformamide of one molar equivalent of a base such as triethylamine, pyridine, quinoline, N-methylmorpholine, Ν, Ν-dimethylaniline at temperatures from -40 ⁰ C to +25 ⁰ C with one mol equivalent of thionyl chloride in an unknown intermediate compound and without isolation in the presence a further molar equivalent of the same bases and in the same solvents with one molar equivalent of the carboxylic acids V, or without further addition of the bases or with up to one molar equivalent of the bases with one molar equivalent of the salts Va or the silyl compounds

f ^ Tf ^ p; p> ~ f; j? "f ~

Vb or Vc at a temperature of -40 ⁰ C to + 30'C ur? The compounds of the general formula XIII can then, if appropriate after removal of the base hydrochloride formed and precipitated in the reaction, by evaporation

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isolate the solvent and optionally by crystallization from inert solvents, or, if the substance is not crystalline by briefly washing with an ethereal or benzene solution, for example an aqueous sodium bicarbonate solution at as deep as possible Clean temperature.

The production of the carboxylic acids modified at the carboxyl group dor general formula XlII can also be done in such a way, dpβ one the carboxylic acids of the general formula V in Presence of the compounds of the general formula Z with a carbodiimide, for example dicyclohexylcarbodiimide, Diisopropylcarbodiimide or N-ethyl-N-3-dimethylaiRinopropylcarbodiimid in a water-containing solvent or solvent mixture, which, for example, acetone, tetrahydrofuran, Dioxane, acetonitrile, dimethylformamide, hexamethyl phosphoric acid triamide, terk-butanol, isopropanol or methyl formate, or in an anhydrous Solvent or solvent mixture which, in addition to the solvents mentioned, also includes dichloromethane, Can contain chloroform, ethyl acetate, ether, benzene, toluene or carbon tetrachloride, in a manner known per se brings to implementation.

The reaction batches for the preparation of the penicillins according to the invention and their salts are worked up throughout in the manner generally known from penicillins.

The one used as a starting material in the present invention 6-aminopenicillanic acid was produced according to known processes by cleavage of penicillin-G, either by fermentative

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Processes or by chemical cleavage (cf.Nlederl. Pat. No. 67/13 809 and German Offenlegungsschrift No. 2 O62 925) won. The carboxylic acids of the general Formula V were derived from the amino acids of the general formula XIV

H ₁ N-CH-COOH XIV

by reacting old the compounds of the general formulas XV, XVI, XVII, XVIII or XIX

AZW, NaC - NY —- N «Z, R ₁ -X —N _ Y - N = Z,

N γ _ N «Z, R ₁ -X —N-

R ₁ R,

XV XVI XVII

R ₁ —c — Ν —Υ —- N * Z, Χ — N - Y — Ν «Ζ,

XVIII XIX

wherein A, B, Q ₁ , Q _x , R ₁ , R _x , X, Y, Z, C and ¥ have the meaning given above, won.

The preparation of the compounds of the general formulas XV, XVI, XVII, XVIII and XIX is in each case in the individual examples described.

The preparation of the compounds of the general formulas VI, VII and IX is described in the literature (cf. J.med. Chem. 2 (1966) p. 980; Ber. Jg6 (1963) p. 2681; Tetrahedron 17. (1962) P. 114). A compound of the general formula VIII was

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from N, N-dimethylethylenediamine after conversion into the N, N bis-trimethylsilyl compound, their reaction with phosgene to give the corresponding cyclic urea and its reaction obtained with phosgene.

Compounds of the general formulas XI and XIa were prepared in the manner described for dimethylformamide (cf. HeIv. I653 (1959)) from the corresponding formamides. The preparation of compounds of the general formulas XII and XIIa is described in the literature (cf. Angew.Chem. 83. (1971) p. 614).

The penicillins according to the invention can also be obtained from the carboxylic acids of the general formula V, their salts of the general Formula Va or its SiIy! Compounds Vb and Vc and 6-aminopenicillanic acid or the silylated 6-aminopenicillanic acids (see the general formulas III and IV) according to the usual methods of peptide chemistry (see E. Schröder, K. Lübke, The Peptide, Methods of Peptide Synthesis, VoI I, Pp. 76-128), but only in a less advantageous way to win,

ψ The non-toxic, pharmaceutically acceptable salts mentioned above include salts of the acidic carboxyl group such as sodium, potassium, magnesium, calcium, aluminum and ammonium salts and non-toxic substituted ammonium salts with amines such as di- and tri-lower alkylamines, procaine, dibenzylamine, N ₁ N -dibenzylethylenediamine, N-benzyl-ß-phenylethylamine, N-methyl- and N-ethylmorpholine, 1-ephenamine, dehydroabietylamine, N, N-bis-dehydroabietylethylenediamine, N-lower alkyl piperidine and other amines that contribute to the formation

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of salts of penicillins siad been used.

In the present invention, the term “lower alkyl” is understood to mean both a straight-chain and a branched alkyl group with up to 6 carbon atoms. In connection with other groups, such as in "U-lower alkylamino", the term "-lower alkyl-" only refers to the alkyl part of the group in question * The chemotherapeutic effectiveness of the new Peniei 1 line has been tested in vivo and in vitro. The in vitro inhibition values (MIC) (see Table 1) were determined in liquid medium in the tube serial dilution test, the reading taking place after incubation at 37 ° C. for 24 hours . The MIC is indicated by the turbidity-free tube in the dilution series. A complete medium with the following composition was used as the nutrient medium:

Lab Lemco (OXOID) 10 g Peptone (DIFCO) 10 g

NaCl 3 g

D - (+) - dextrose (MERCK) 10 g buffer pH 7.4 1000 ml

The spectrum of activity includes both gram-negative and Gram positive bacteria. The particular advantage of the invention Penicillins are due to the fact that they are resistant to ampicillin and carbenicillin both in vitro and in animal experiments Bacteria of the Klebsiella-Aerobacter group, against

Minimal inhibitory concentration

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Ampicillin and Carbenicillin Resistant Indole Positive Proteus and Providencia bacteria, ampicillin and carbenicillin resistant Escherichia coli strains resistant to carbenicillin Pseudomonas aeruginosa and Serratia marcescens bacteria are effective.

The generally excellent effect is achieved both with a single and with multiple administration. The invention Penicillins are stable to stomach acid. Some of the new penicillins are excellently tolerated, what This is made particularly clear by the extremely high dose that, in these cases, is administered intravenously to mice in the Tail vein is tolerated without complications.

The penicillins according to the method can be formulated and administered alone or in combination with a pharmaceutically acceptable carrier substance according to the usual pharmaceutical procedure. For oral administration they may be in the form of tablets which may contain, for example, in addition starch, lactose, certain types of clay, etc. w or in the form of capsules, drops or granules, given alone or together with the same or equivalent additives. They can also be given orally in the form of juices or suspensions, which may contain flavor corrections or colorants customary for such purposes.

Furthermore, the penicillins according to the method can by parenteral Application, e.g. intramuscular, subcutaneous or intravenous, possibly as a continuous drip infusion.

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In the case of paxenteral administration, this happens on best as a sterile solution with other components of the solution such as sodium chloride or glucose to make the solution isotonic. To prepare such solutions, you can expediently use these penicillins in the form of dry ampoules. For oral and parenteral administration is a dosage of 25,000 to 1 hill. E / kg body weight / day is appropriate. *)

You can get it as a single dose, or as a continuous drip or also give in several doses. For a local treatment, the penicillins according to the method can be used as Prepare and apply ointments or powder.

The following examples are intended to illustrate the invention without limiting it.

The ß-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 0D solution; the signals given in the examples correspond to the T "scale; they correspond to the respective constitution. The water content of the penicillins was taken into account when calculating the analytical values.

E «units; 1 mole of a penicillin has 5,951 ^ χ ΙΟ ⁸ E.

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Experimental part example 1

A ♦) D-α [(3-Methylsulfonyl-imidazolidin-2-on-1-yl) -carbonylamino] -benzylpenicillin - sodium;

CH ₃ -SO ₂ -N N-CONH-CH-CONH-j

COONa

6.8 parts by weight of da - [(3-methylsulfonyl-imidazolidin-2-on-1-yl) carbonylamino] phenylacetic acid were dissolved in 40 Vol.TIn. Methylene chloride brought under addition of a little tetrahydrofuran in the solution, cooled to <-40 ^e C and under vigorous stirring with 2.0 wt. Tln. N-methylmorpholine added. This was followed by the also -40 ⁰ C cold solution of 3.75 Gew.TIn all at once. Tetramethylchlorformamidinium chloride in 15 Vol.TIn. Methylene chloride was added with vigorous stirring, the mixture was stirred for 5 minutes at -40 ° C. and then combined with the solution of 4.7% by weight tin, which was cold and kept at pH 2.5, at ^{0 ° C.} 6-aminopenicillanic acid in 30 Vol.TIn. 80 tiger aqueous tetrahydrofuran. The pH of the mixture was maintained at 2.5 by adding more N-methylmorpholine. The mixture was stirred for 30 minutes without cooling, the pH still being kept at 2.5. Then 40 Vol.TIn. Water was added, then the pH was adjusted to 7, methylene

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chloride and tetrahydrofuran removed on a rotary evaporator, the solution once with 50 Vol.TIn. Extracted ethyl acetate and the aqueous phase is covered with fresh ethyl acetate. While stirring and cooling with ice, the mixture was acidified to pH = 1.5 with dilute hydrochloric acid, the ethyl acetate was separated off, the aqueous phase was extracted a further 2% with ethyl acetate, the combined organic phases were washed with water and dried over MgSO ₄ . It was then filtered, with 20 Vol.TIn. a molar solution of sodium 2-ethylhexanoate in methanol-containing ether is added, the mixture is evaporated to almost dryness in vacuo, the residue is dissolved in the necessary amount of methanol and the sodium salt of penicillin is precipitated by adding 10 times the amount of absolute ether with shaking. It was filtered off with suction, washed thoroughly with absolute ether and dried over P ₂ O ₅ in a vacuum desiccator.

Yield: 84 56

ß-lactam content: 74 Ί »

Calculated: C 43.4 H 4.8 N 11.3 S 10.4 Found: C 43.4 H 5.4 N 11.3 S 10.3 IR bands at 3325, 3055, 3025, 3002, 2965, 2924, 2865

1771, 1738, 1679, 1610, 1529, 1398 and 1171 cm "" ¹ . NMR signals at T = 2.3-2.8 (5H), 4.4 (IH), 4.5 (2H), 5.8 (IH),

6.15 (4H), 8.4 (3H) and 8.5 ppm (3H).

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B. 1.) D-α- [_ (3-Methylsulfonyl-imidazolidin-2-one ~ l-yl) ■ carbonylaminoj -phenylacetic acid:

CH ₃ SO ₂ -N N-CONH-CH-COO ?!

^{3 2} V_V I

16.6 parts by weight (D -) - C-phenylglycine were dissolved in 150 Vol.Tin = 50% aqueous dioxane with the addition of a sufficient amount of 2 η sodium hydroxide solution. The solution was then reset to pH = 7.5 by adding 2η hydrochloric acid, with the amino acid partially separating out again in finely divided form. Then 1-chlorocarbonyl-3-methylsulfonyl-imidazolidone- (2) was added in portions while cooling with ice, and the pH of 7.5 was maintained by simultaneously adding 2 η sodium hydroxide solution. The mixture was stirred without cooling until the pH remained constant at 7.5 even without the addition of sodium hydroxide solution (about 10 minutes). Then with 50 Vol.TIn. Water is added, the mixture is concentrated to half the original volume on a rotary evaporator and once with 50 Vol.TIn. Extracted ethyl acetate after unreacted C-phenylglycine had been filtered off. The mixture was then acidified to pH = 2, extracted several times with ethyl acetate, the combined ethyl acetate phases were washed with water, dried over MgSO ₄ , filtered, evaporated to dryness and recrystallized from acetone / nitromethane. Mp. = 25O ⁰ C

Le AU 038 - 28 -

30981 7/1174

Yield: 56%

Calculated: C 45.7 H 4.4 N 12.3 S 9.4

Found: C 45.7 H 4.5 N 12.3 S 9.2

IR bands at 3345, 36 (X) -2300, 1731, 1652, 1538, 1210 and (in Nujol) 1168 cm " ¹ .

NMR signals at? "= 1.2 (IH), 2.55 (5H), 4.6 (IH), 6.2 (4H),

and 6.6 ppm (3H).

2.) D, L-α-L (3-methylsulfonyl-imidazolidin-2-on-1-yl) -carbonylaminoj -4-chloro-phenylacetic acid:

CH ₃ SO ₂ -N N-CONH-CH-COOH

Cl

This carboxylic acid was described in Example 3Bl Way from 5.8 wt. Tin. 4-chloro-C-phenylglycine and 6.8 wt. TIn. 1-chlorocarbonyl-3-methylsulfonylimidazolidone (2). (

M.p. = 190 ^° C

Yield: 88%

Calculated: C 41.6 H 3.7 Cl 9.4 N 11.2 S 8.5 found: C 40.8 H 3.7 Cl 9.2 N 11.1 S 8.9

IR bands at 3700-2200, 3310, 1730, 1654, 1540 and 1168 cm " ^1. (In Nujol)

NMR signals atir = 1.1 (IH), 2.55 (4H), 4.5 (IH)

6.1 (4H) and 6.65 ppm (3H)

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3.) D, L-β-1_ (25-methylsulfonyl-imidazolidin-2-on-l-yl) carbonylaminoj - «- thienyl ~ (2) -acetic acid:

CH ₃ SO ₂ -I ("N-CONH-CH-COOH

This carboxylic acid was in the example IBl

5 5
described way from ^ wt. TIn, a-thienyl- (2) -glycine and 6.8 wt. Tin. l-chlorocarbonyl-3-methylsulfonyl-imidazoldin (2).
Yield $ 88>.
Mp. Approx. 110 ⁰ C ₃ crude product,
Calculated C 38.0 H 3.8 N 12.1 S 18.4 found: C 38.2 H 4.8 N 10.8 S 17.9 IR bands at 3600-2200, 3315, 1740, 1725, 1664 , 1525 (in NuJoI) and 1170 cm " ¹ .

NJK signals at? "= 1.2 (IH), 2.4-3.1 (3H), 4.2 (IH),

6.07 (4H) and 6.67 ppm (3H).

4.) L-a-I (3-methylsulfonyl-imidazolidin-2-on-l-yl) -carbonylaminoj-phenylacetic acid:

A (L +)
CH ₃ -SO ₂ -N N -CO-NH-CH-COOH

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This carboxylic acid was prepared in the manner described in Example 1 B 1 from 5.3 wt. Tin, (L +) -OPhenyl! Glycine and 6.8 wt. Tin. l ~ chlorocarbonyl-3 ~ methylsuli; onyl ~ imidazolidone2).
Mp = 245 ^° C

Calculated: C 45.7 H 4.4 N 12.3 S 9.4 found: C 44.9 H 4.5 N 11.9 S 9.4 IR and NMR spectra are identical to those of the product of Example 1, Bl.

5,) D, L-α- j_ (3-methylsulfonyi-imidazolidin-2-one-l-yl) -carbonylaminoj-2,6-dicblorphenyl acetic acid

CH ₃ -SO ₂ -N N-CONH-CH-COOH

This carboxylic acid was in the manner described in Example 1 B 1 from 7.7 wt. TIn, 2,6-D.ichlor-C-phenylglycine and 6.8 wt. Tin. 1-chlorocarbonyl-3-methylsulfonylimidazolide on (2).

Mp> 260 ° C
Yield: 69%

IR bands at 3400-2200, 3290, 1742, 1714, 1646, 1580, 1522, (in Nujol) 1260, 1170, 1130, 783 and 763 cm " ^1. NMR signals at 0.9 (IH), 2.4-2.65 (3H), 3.4 (IH),

5.8-6.2 (4H) and 6.65 ppm (3H),

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6.) L-α- [(3 ~ acetyl-imidazolidin-2 ~ on-l-yl) -carbonylamino] -phenylacetic acid:

CH ₃ CO-N N-CONH-CH-COOH

N N

This carboxylic acid was prepared _{in the manner described in Example 1 f} Bl. From 5.0 wt. TIn. (L +) - C-phenylglycine and 5.7 wt. TIn. l-chlorocarbonyl ~ 3 ~ acetyl-imidazolide2).

Mp = 214 ^C C
Yield: 69%

calculated? C 55.0 H 4.9 N 13.8 found: C (53.5) H 5.2 N 13.7 IR bands at 3650-2250, 3300, 1735, 1665 and 1252 cm "" ¹ , (in Nujol)

NMR signals at T ^ = 1.0 (IH), 2.3-2.8 (5H), 4.5 (IH), 6.2 (4H)

and 7.6 ppm (3H).

7.) D, L-α- [(3-Acetyl-imidazolidin-2-on-l-yl) -carbonylamino] -4-chloro-phenylacetic acid:

Λ '■

CH ₃ CO-N N-CO-NH-CH-COOH

Le A 14 038 - 32 -

3098 1 7/1 1 7

■ This carboxylic acid was in the manner described in Example IBl from 6.2 wt. TIn. D, L-4-chloro-C ~ phenyl glycine and 5.7 wt. Tin. l-chlorocarbonyl - ^ - acetyl-imidazolidone (2) produced.
P.p. 194 ° C
Yield: 53%

calculated; C 49.5 H 4.1 Cl 10.4 N 12.4 found: C 49.6 H 4.6 Cl 9.4 N 12.2 IR bands at 3700-2300, 3290, 1725, 1685, 1648 and (in Nujol) 1252 cm " ¹ .

NMR signals are 0.9 (IH), 2.55 (4H), 4.45 (IH),,

6.2 (4H) and 7.55 ppm (3H).

8.) D, L-ce- [(3-Acetyl-imidazQlidin-2-on-1-yl) -carbonylaminoj -4-methylphenyl acetic acid

CH ₃ CO-N N-CONH-CH-COOH

CH,

This carboxylic acid was described in Example IBI Way from 5.4 wt. TIn. 4-methyl-C-phenylglycine and 5.7 wt. Tin. l-chlorocarbonyl-3-acetyl-imidazolidone) manufactured.

Yield: 42 56

IR bands at 3600-2200, 3310, 1738, 1712, 1678, I666 and

(in Nujol) 1256 cm " ¹ .

Ie AU 038 - 33 -

309817/1174

NMR signals at * = 1.0 (IH), 2.6 (2H), 2.8 (2H), 4.5 (IH), (in acetone-d ₆ ) 6.2 (4H), 7.6 (3H) and 7.7 ppm (3H).

9.) D, L-OC- [(3-Acetyl-imidazolidin-2-one ~ l-yl) -carbonylamino] -a-thienyl- (2) -acetic acid:

This carboxylic acid was described in Example IBI Way from 8.6 wt. TIn. Thienyl - ^ - acetic acid and 9.5 wt. TIn. l-chlorocarbonyl-J-acetyl-imidazoli don (2) manufactured.

Mp 197 ° C
Yield: $ 62>

Calculated: C 46.3 H 4.2 N 13.5 S 10.3 Found: C 47.1 H 4.4 N 13.8 S 9.7

IR bands at 3280, 3080, 3450-2300, 1728, 1680, 1652, 1522, (in NuJoI) 1260 and 705 cm " ¹ .

NMR signals at T ^ 1.1 (IH), 2.5-3.2 (3H), 4.2 (IH), 6.2 (4H)

and 7.6 ppm (3H).

10.) D, L-a-I (3-acetyl-imidazolidin-2-on-1-yl) ~

carbonylaminoj -2,6-dichloro-phenylacetic acid:

CH ₅ -CO-N N-CONH-CH-COOH

Ie A 14 038 - 34 -

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This carboxylic acid was described in Beipsiei I ß 1 Way from 6.7 wt. TIn. 2,6-dichloro-C-phenylglycine and 5.3 wt. TIn. l-Chlorcarbonyi-S-acetyl-imidazolidone 2) manufactured.

Mp = 250 ^° C
Yield? 74 i »

Calculated: C 44.9 H 3.5 Cl 19.0 N 11.2
found: C 45.2 H 3.7 Cl 18.5 N 11.4
IR bands at 3600-2200, 3302, 1735, 1682, 1.625, 1520
(in NuJoI) and 1255 cm " ¹ .

NMR signals at T = 0.7 (IH), 2.3-2.7 (3H), 3.4 (IH), 6.2 (4H)

and 7.6 ppm (3H).

C.) l-Chlorocarbonyl-3-methylsulfonyl-imidazolidone ('2):
0

CH ₃ SO ₂ -N N -COCl
V- /

16.4 wt. l-Methylsulfonyl-imidazolidone (2) were in dioxane for 3 days with 27 wt. TIn. Trimethylchlorosilane and
20 wt. TIn. Boiled triethylamine. The precipitated triethylamine hydrochloride was filtered off, and 11 parts by weight of tin were added. Phosgene and left to stand at room temperature overnight. It was then evaporated to dryness and recrystallized from boiling acetone. Yield 70%.
Mp = 178 ^° C

Calculated: C 26.5 H 3.1 Cl 15.7 N 12.4 S 14.1
found: C 27.2 H 3.4 Cl 15.3 N 12.0 S 14.1

Le A 14 038 - 35 -

309817/117 4

NMR signals at ¹ ^ = 5.6 -6.2 (4H), and 6.6 ppm (3H). IR bands at 3010, 1807, 1721, 1360, 1165, 984 and 742 cm " ¹ .

The same product can also be easily prepared from 1-methylsulfonylimidazolidone (2) and produce excess phosgene in methylene chloride in the presence of pyridine.

D.) N-Methylsulfonyl-imidazolidon-2:

CH ₃ -SO ₂ -N NH

Regulation 1.

For the suspension of 43 wt. TIn. Imidazolidone — 2 in & 00 Vol. TIn. 63 parts by weight of dry tetrahydrofuran were added dropwise at room temperature. Methanesulfochloride, stirred for 1 hour at 30-40 ° C. and then refluxed for 1 hour. Subsequently, the solvent was distilled i.Vak.ab and held for 1 hr. At 60 ⁰ C on the oil pump. The residue was recrystallized from warm acetone. ^l
Yield: 25% melting point = 193 ^° C.
Calculated: C 29.3 H 4.9 N 17.1 S 19.5 found: C 29.0 H 5.0 N 17.2 S i ⁽ i, 6 IR bands at 3250, 3115, 1715, 13th. ^c ic and 11.60 cm " ^1. NMR signals at?" = 2.4 (IH), 6.2 U ^TI , 6.5 (2H) and

6.8 ppm (3H).

Le Λ 14 050 - 36 -

: j 0 9 8 1 7/1 1 7 /.

Regulation 2. ~ 3> -

For the suspension of 43 wt. TIn. Imidazolidon-2 in 300 vol. TIn. 80 parts by weight of dry tetrahydrofuran were added dropwise in the course of 30 minutes with stirring. Methanesulfochloride and then 56 parts by weight. Triethylamine so that the internal temperature was 35-4O ° C. The mixture was stirred for 2 hours at 45 ^° C., the solvent was then drawn off in vacuo, the remaining residue was extracted 2 with 150 vol. TIn each time. Chloroform and recrystallized the remaining crystals from methanol.

Yield: 49%. The product is correct according to its mp and IR spectrum with the N-methylsulfonylimidazolidone-2 described above match.

Example 2

D, L-OC- [(3-Methylsulfonyl-imidazolidin-2-on-l-yl) -

carbonylamino] -4-chlorobenzylpenicillin sodium:

CH ₃ SO ₂ -N N-CONH-CH-COF "-— ^ ^ - ^υ "'

COONa

Cl
This penicillin was prepared in the manner described in Example 1A from 7.5 wt. Tin. D, L-oc- [(3-methylsulfonylimidazolidin-2-on-1-yl) carbonylaminoJ-4-chlorophenylacetic acid, 3.75 wt. Tin. Tetramethylchlorformamidinium chloride and 4.7 wt. TIn. 6-aminopenicillanic acid produced. Instead of N-methylmorpholine, 2.02 wt. TIe. Triethylamine used.

Le AH 038 - 37 -

309817/1 174

2152988

Yield: 65 Ί » *. $ 3 ^

ß-lactam: 62 i>

On the basis of the NMR spectrum, the product still contained 24 # methylsulfonylimidazolidonyl-carbonylaminoehlorphenylessigsäure which, however, can be removed by fractional acidification of the aqueous solution of the penicillin sodium salt. IR bands at 3310, 1760, 1722, 1670 * 1605 and 1170 cm "" ¹ . (in NuJoI)

NMR signals at = 2.53 (2H), 2.67 (2H), 4.4 (IH), 4.5 (2H), (in methanol d _h ) [5.8 (1H), 6.1 (4H), 6, 65 (3H), 8.3-8.5 ppm

(6H).

Example 3

D, L-oc [(3-Methylsulfonyl-imidazolidin-2-on-l-yl) -carbonyl-aaino] -α-thienyl- (2) -methylpenicillin-sodium:

CH ₃ SO, -K N-

COONa

This penicillin was in the manner described in Example 1A from 7.0 wt.TIn. D, La- | j3-Methylsulfonyl-imidazolidin 2-on-1-yl) -carbonylaminoJ-α-thienyl- (2) -acetic acid, 3.75 wt. Tin. Tetramethylchlorformamidinium chloride and 4.8 wt. TIn. 6-aminopenicillanic acid divides herges.
Yield: 38 #
ß-lactam content: $ 68>

IR bands at 3310, 1758, 1722, 1650, 1605 and 1170 cm " ^1. NMR signals at T = 2.5-3.1 (3H), 4.1-4.6 (3H), 5.8 (IH),

6.1 (4H), 6.7 (3H) and 8.25-8.5 ppm (6H).

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The crude product contained after about "30 f> sodium-D, La | (3-methylsulfonyl-inida2olidin-2-on-l-yl) ~ carbonylaminola-thienyl- (2) acetate, which, however, by fractional acidification of the aqueous Lets remove the solution.

Example 4

L-a- [(3-Methylsulfonyl ^ imidazolidin-2-on-1-yl) carbonylaminoj -benzylpenicillin sodium:

; -SO ₂ -if NI

(S)
CH, -SO.-N N-CONH-CH-CONB

COONa

This penicillin was prepared in the manner described in Example 1A from 6.8 wt. TIn. L-ap3-methylsulfonyl-imidazolidin-2-one-l-yl) carbonylamino] phenylacetic acid, 3.75 wt. Tin. Tetramethylchloroformamidinium chloride and 4.7 parts by weight of 6-aminopenicillanic acid.
Yield: $ 72
ß-lactam content: 66 fi

Calculated: C 44.1 H 4.7 N 11.5 S 10.6 found: C 43.5 H 5.5 N 11.5 S 10.1 When calculating the analytical values, a water content of 3% and a content of sodium 2-ethylhexanoate of ' 2 1' is taken into account.

IR bands at 3310, 1760, 1722, 1665, 1602 and 1168 cm "" ¹ NMR signals at T = 2.6 (5H), 4.35 - '*. 8 (3H), 5.8 (IH),

6.2 (4H), 6.7 (? H) and Qk ppm (6H). -

:. ' 0 9 8 1 7 / '1 1 7 /,

Example 5

D, L-α- Γ (3-methylsulfonyl-iniidazolidin-2 ~ on-1-yl) ~ carbonylaminoJ-2,6-dichloro ~ benzylpenioillin-sodium:

, - ^ Λ. CH.

CH ₃ -SOg-N N-CONH-CH-CONH-j-

COONa

■ 3
■ '"! Kr X

Cl. Α., Cl

This penicillin was prepared in the manner described in Example IA from 7.0 wt. TIn. D, L-oc- {"(3-methylsulfonyl-imidazolidin-2-on-1-yl) carbonylamino] -2, o-dichlorophexyl acetic acid, 3.2 parts by weight of tetramethylchloroformamidinium chloride and 4.3 parts by weight of 6-aminopenicillanic acid. the reaction of the substituted phenylacetic acid with the Tetramethylchlorformamidiniumchlorid, however, was not carried out as in example 1 A, at -40 ⁰ C but at -20 ⁰ C, yield: 77 fi
β-lactam content: 61.5 fi

Calculated: C 38.5 H 4.0 Cl 12.2 N 10.0 S 8.7 found: C 36.0 H 4.0 Cl 12, b N 10.5 S 9.3 IR bands at 3310 , 1764, 1720, 1678, 1607, 1512, 1255 and (in Nujol) 1167 cm "" ¹

NMR signals at T = 2.5-2.9 (3H), 3.8 (IH), 4.45 (2H), 5.8 (IH)

6.15 (4H), 6.7 (3H) and 8.3-8.6 ppm (6H),

When calculating the analytical values, a content of 62 56 penicillin, 30 # α- [(3-methylsulfonyl-imidazolidin-2-on-l-yl) -carbonylamino] -2.6-dichloro-pheriylacetic acid sodium, 4.0 $ sodium 2-ethylhexanoate and 3.6% water

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based on. These contents result from the NMR spectrum of the raw product. The penicillin can be removed by fractional acidification of the aqueous solution of the crude product win in pure form.

Example 6

A.) L-QC- R3-Acetyl-imidazolidin-2-on-1-yl) -carbonylaminoj benzylpenicillin-sodium :

CH ₅ CO-N _x N-CONH-CH-CONH-T-j ^ Y " ³

CH ₃

0 ''

COONa

This penicillin was in the manner described in »Example 1 A from 5.0 wt. TIn. La - [(3-Acetyl-imidazolidin-2-on-l-yl) -carbonylaminoj-phenylacetic acid, 3.Ϊ wt. TIn. Tetramethylchloroformamidinium chloride and 4.3 wt. TIn. 6-aminopenicillanic acid produced.
Yield; $ 74
ß-lactam content: 75 ί>

IR bands at 3305, 1765, 1730, 1675, 1605, 1520 and 1258 cm " ^1. Cin NuJoI)

NWR signals at-C = 2.4-2.8 (5H), 4.5-4.8 (3H), 5.8 (IH),

6.22 (4H), 7.5 (3H) and 8.4 ppm (6H),

B.) 3-Acetyl-imidazolidin-2-one-1-carbonyl chloride;

0
CH ₃ -CO-N Ίϊί-COCl

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20 wt. Tie. N-acetyl-imidazolidones were iui mixture with 25 wt. Tin. Triethylamine and 150 vol. Tin. Submitted dry benzene and in the course of 30 minutes with stirring at room temperature with 27 wt. TIn. Trimethylchlorosilane in 40 vol. TIn. Benzene was added dropwise. The mixture was then refluxed for 18 hours with exclusion of moisture and, after cooling, the precipitated triethylamine hydrochloride (22 parts by weight = 100%), which was carefully washed out with dry benzene, was filtered off. The benzene solution thus obtained was added at 5 ⁰ C with a solution of 17 wt. Tln. Phosgene in 50 vol. TIn. Benzene was added and the mixture was left to stand ^{at 5 ° C. overnight.} The solvent was then removed in vacuo and the residue was dried on an oil pump. It was recrystallized from acetone / pentane mixture. Yield: 81 <f> mp = 104 ° C.
Calculated: C 37.7 H 3.7 Cl 18.6 N 14.7 found: C 39.3 H 4.3 Cl 17.7 N 14.7 IR bands at 1798, 1740, 1690 and 1660 cm " ¹ , IMI signals at tr = 5.65-6.3 (4H) and 7.45 ppm (3H). According to the NMR spectrum, the product still contained 5-10% N-acetylimidazolone, which, however, when reacted with C-phenylglycine and others Amino acids (as in Example 1, B6.) Does not interfere.

C.) N-acetyl-imidazolidone-2

CHjCO-N NH

Le A 14 038 - 42 -

3.0-98 1 7/1 174

For the suspension of 25.8 wt. Tin. ImidazoIun-2 in 350 Vol. TIn. of dry tetrahydrofuran was added dropwise over 60 minutes at 0 ⁰ C 23.6 wt. TIe. Acetyl chloride in 100 vol. TIn. Tetrahydrofuran. The mixture was stirred for 3 hours at room temperature, then dry air was blown through the solution for a while, then the solvent was removed in vacuo and the residue was recrystallized from boiling in nitromethane. Yield: 52% m.p. 188 ° C calculated: C 46.9 H 6.9 N 21.9 found: C 47.0 H 6.2 N 22.5 IR bands at 3230, 1730 and 1640 cm "* ¹ NMR signals at T = 6.2 (2H), 6.5 (2H) and 7.6 ppm (3H).

Example 7

D, L-oc- j (3-acetylimidazolidin-2-one-l-yl) - carbonylaminoj 4-chlorobenz / 'ylpenicillin sodium:

Λ (R, S) _{Q CH}

-CONH-CH-CONH _n -T ^ ν /

JK / Vh fγ CH,

COONa

This penicillin was described in Example 1A Way from 4.0 wt. Tin. D, L-oc [(3-acetylimidazolidin-2-on-l-yl) -carbonylaminoj-4-chlorophenylacetic acid, 2.2 wt. TIn. Tetramethylchloroformamidinium chloride and 3.25 wt. TIn. 6-aminopenicillanic acid produced.

Le AU 038 - 43 -

309817/1174

Yield: $ 76> ι · ι

β-lactam content: 89 # IR bands at 3310, 1760, 1730, 1670, 1600, 1518 and

(in NuJoI) 1259 cm " ¹ .

NMR signals at T- 2.4-2.9 (4H), 4.4 (IH), 4.5 (2H),

5.8 (IH), 6.2 (4H), 7.5 (3H) and 8.3 -

8.5 ppm (6H).

Example 8

D, L-OC-1 (3-Acetyl-imidazolidin-2-on-l-yl) -carbonylaminol -4-methyl-benzylpenicllline-sodium:

9

^W. Ά (R _t S)

CH ₃ CON N-CONH-CH-CONH-j- < ^ , ^CH s

II ..

COONa

CH ₃

This penicillin was described in Example 1A

Way from 3.2 wt. TIn. D, L-oc ~ [(3-acetyl-imidazolidin-2 ~ one-

1-yl) carbonylamino-4-methylphenylacetic acid, 1.9 wt. TIn.

Tetramethylchlorformamidinium chloride and 2.6 wt. TIn, 6-aminopenicillanic acid manufactured.

Yield: 45 %

ß-lactam content: 83 #

IR bands at 3305, 1760, 1725, 1672, 1600, 1515 and

(in Nu j oil) 1255 cm "* ¹ .

NMR signals at T = 2.6-2.8 (4H), 4.4-4.8 (3H), 5.8 (IH),

6.2 (4H), 7.5 (3H), 7.7 (3H) and 8.3-

8.6 ppm (6H).

Le A 14 038 ~ 44 -

309817/1174

Example 9 ^ MS ^

D, L-a- (3-Acetyl-imidazolidin-2-on-1-yl) -carbonylaminoJ-athienyl - (2) -methylpenicillin sodium:

/ X (R, S) CH ₃ CO-N N-CONH-CH-CONH-j K ^ v,  ^CH 3

COONa

This penicillin was described in Example IA Way from 8 GeA. TIn. D, L-a- (3-Acetyl-imidazolidin-2-onl-yl) -carbonylaainoJ-thienyl- (2) -acetic acid, 4.9 wt. TIn.

Tetramethylchlorformamidinium chloride and 6.5 wt. TIn. 6-

Aminopenicillanic acid produced.

Yield: 88 %

.beta.-lactam: 87 i> IR bands at 3302, 1760, 1732, 1678, 1605, 1520, 1315 and (in NuJoI) 1261 cm ^'1.

NMR signals at = 2.5-3.2 (3H), 4.0-4.5 (3H), 5.8 (IH),

6.2 (4H), 7.5 (3H) and 8.2-8.6 ppm (6H).

Example 10

D, L-OC-J (3-Acetyl-imidazolidin-2-on-1-yl) -carbonylamino | -2,6-dichlorobenzylpenicillin sodium:

■ Λ

! H ₃ CO-If ϊ

CH, _{ν 7}

egg ι egg

COONa

Le A 14 Q38 - 45 -

309817/1 174

This penicillin was prepared in the manner described in Example IA from 6.5 wt. TIn. D, La - [(3-Acetyl-imidazolidin-2 ~ on-1-yl) -carbonylaminoj -2,6-dichlorophenylacetic acid, 3.2 wt. Tin. Tetramethylchlorformamidinium chloride and 4.3 wt. TIn. 6-aminopenicillanic acid produced. The Umeetzung of the substituted phenylacetic acid was carried out with the Tetramethylchlorformamidiniumchlorid at -10 ⁰ C. Yield: 29 %
ß-lactam content: 66 56

IR bands at 3310, 1765, 1735, 1685, 1615, 1520, 1265, (in Nujol) lloo, 1028 and 805 cm. NMR signals at T = 2.7 (3H), 3.8 (IH), 4.3-4.6 (2H), 5.8 (IH),

6.2 (4H), 7.5 (3H) and 8.2-8.6 ppm (6H).

According to the NMR spectrum, the crude product contained 27 % sodium D, La (3-acetylimidazolidin-2-on-1-yl) carbonylamino] -2,6-dichlorophenylacetic acid, which was obtained by fractional acidification the aqueous solution can be removed from the product.

Example 11

D-α [(3-ethylsulfonyl-imidazolidin-2-one-l-yl) -carbonylaminoj benzylpenicillin sodium:

CO. fr> \ g

Qo _{x (R)}

C _a H ₉ -SO ₄ -N N-CO-NH-CH-CO-NH

₁ - ζ

COONa

Le A 14 038 - 46 -

309817/1174

There were 2.9 wt. Tie. D-α [(3-AethylsuiionyJ.-imidazolidin-2-on-l-yl) -carbonylaaino] phenylacetic acid (the substance containing 1 mole of isopropanol and 1 mole of H _t 0 in the crystal) in 30 by volume tin. Tetrahydrofuran dissolved. The solution was then cooled to -30 ^# C and the cooled to -40 ⁰ C solution of 1.6 wt. Tln. Tetraethyl chloroformamidinium chloride in 30 vol. TIn. Dichloromethane combined. Then the mixture to -25 ^e C Tl was placed, 0.9 wt. ^4, N-methylmorpholine and, after 3 minutes, a cooled to -5 * C mixture of 2.3 wt. Tln. 6-aminopenicillanic acid and 25 vol. TIn. 90 # aqueous tetrahydrofuran, which was adjusted to pH 2.5 with about 10 # hydrochloric acid, added. The temperature was then allowed to rise to 0 ° C. and the pH of the mixture was kept at 2.5 by adding N-methylmorpholine or dilute sodium hydroxide solution accordingly. After 1 hour, it was no longer necessary to add a base to maintain the pH 2.5. The pH was then adjusted to 7.0, most of the tetrahydrofuran was removed in vacuo, the remaining aqueous solution was shaken out once with ether (the ether phase was discarded) and, after being layered with an ether-ethyl mixture, acidified to pH 1.5. The organic phase was separated off, washed with water and dried over MgSO ₄ at 0 ° C. for 1 hour. Then the desiccant was removed and a methanol-containing ethereal solution of sodium 2-ethylhexanoate of the sodium salt of penicillin was precipitated.

Yield: 3.2 parts by weight. ß-lactam content: 81.9 J *.

NMR signals at T = 2.4-2.85 (5H), 4.4-4.8 (3H), 5.8 (IH),

6.15 (4H), 6.3-6.7 (2H) and 8.3-8.8 ppm

D-α £ (3-AethylBulfonyl-imidazolidin-2-on-1-yl) -carbonylaminoJphenylacetic acid:

Le AU 03 8 - 47 -

309817/1174

/ Λ ^(D)

C ₂ H ₅ -SO ₂ -N Ji-CO-NH-CH-COOH

To a solution of 5 _f 5 wt. TIn. D-bis-trimethylsilyl-aminophenylacetic acid in 40 Vol.TIn. Carbon tetrachloride were added at about 0 ⁰ C 4.5 wt. TIe. 3-Aethylsulfonyl-imidazolidin-2-one-1-carbonyl chloride was added, the mixture was then left to ^{stand for 4 hours at 20 °} C., the solvent was then drawn off and the residue was thoroughly processed with 1 HCl in a mortar. The solid product was filtered off with suction, washed with water, dried and recrystallized from isopropanol. Yield: 6.0 parts by weight.

Mp = 102 ° (solidifying again, then) Mp = 211 ° (heating bench) The content of one mole of isopropanol and one mole of H ₂ O was taken into account in the calculated analytical data: calculated: C 47.1 H 6.3 N 9.7 S 7.4 found: C 47.1 H 5.7 N 9.7 S 7.6 NMR signals at T = 2.6 (5H), 4.6 (IH), 6.1 ( 4H), 6.3-6.7 (2H)

and 8.5-8.7 ppm (3H).

3-ethylsulfonyl-imidazolidin-2-one-l-carbonyl chloride:

"^ Cl

Le AU 038 - 48 -

309817/1 1 74

This product was prepared from 3-ethylsulfonyl-imidazolidin-2-one and phosgene in dichloromethane and in the presence of pyridine at 20 ⁰ C. Mp = 174 ° calculated: C 29.9 H 3.8 Cl 14.8 N 11.6 S 13.3 found: C 30.1 H 3.8 Cl 14.7 N 11.8 S 13.3 NMR Signals at T = 5.5-6.1 (4H), 6.2-6 * 65 (2H) and

8.4-8.75 ppm (3H).

l-ethylsulfonyl-imidazolidin-2-one:

, A

CH ₅ -SOa-N NH \

This substance was made by heating molar amounts of imidazolidin-2-one and ethylsulfonyl chloride at 150 ° to 180 ° (until the evolution of HCl has ended). The pure substance was obtained by extraction with hot benzene, acetone and ethyl acetate from the crude product and recrystallization from acetone (with the addition of activated charcoal). M.p. = 114 "Calculated: C 33.7 H 5.7 N 15.7 S 18.0 found: C 33.1 H 5.7 N 16.3 S 17.7 NMR signals at T = 5.9-6.7 (6H) and 8.5-8.8 ppm (3H).

Example 12

D-α- (3-ethylsulfonyl-imidazolidin-2-on-l-yl) -carbonyl- -amino-benzylpenicillin sodium:

Le AU 038 - 49 -

309817/1

CH «-SO _a -N N-CO-NH-CH-CO-NH ₁ - S

COONa

The solution of 8.6 wt. Tin. D-Bis-trimethylsilyl-a-aminophenylacetic acid in dichloromethane was cooled to 0 ⁰ C, then the solution of 7.0 wt. Tln. 3-Aethylsulfonyl-imidazoiidin-2-one-1-carbonyl chloride in 15 vol. TIn. Dichloromethane is added dropwise with further cooling and the mixture was then let stand overnight at 0 ⁰ C. Then the solution of 5.0 wt. TIn. Tetramethylchlorformamidinium chloride in 15 vol. TIn. Dichloromethane was added and the mixture was left to stand at 0 ° for 1 hour. Then this reaction mixture was cooled to 0 ° C and brought to pH 2.5 with dilute hydrochloric acid, suspension of 8.2 wt. TIn. 6-aminopenicillanic acid in 85 vol. TIn. 80 Seigern aqueous tetrahydrofuran was added dropwise while keeping the pH at 2.5 by adding dilute NaOH. The mixture was then stirred for a further 1 hour at 0 ^° C. and, if necessary, the pH was kept at 2.5 by adding more dilute sodium hydroxide solution. The pH was then adjusted to 7.0, the volatile organic solvents were removed in vacuo and the sodium mixture of penicillin was isolated in the manner described in the previous example.
Yield: 8.0 parts by weight.
ß-lactam content: 58 56

Le A 14 038 - 50 -

30981 7/1174

Example 13 - S 4

α (3-Aethylsulfonyl-imidazolidin-2-on-1-yl) -carbonylamino | -p-chlorobenzylpenicillin sodium:

Cn
C ₁ H ₅ -SO ₂ -N N-CO-NH-CH-CO-NH-fY ^ V / ^CH *

CH ₃ COONa

This penicillin was prepared in the manner described in Example 11 from 4.5 wt. TIn. α JJC3-ethylsulfonyl-imidazolidin-2-one-l-yl) carbonylaminoj-p-chlorophenylacetic acid, 2.3 wt. Tin. Tetramethylchloroformamidinium chloride, 1.3 wt. TIn. N-methylmorpholine and 3.2 wt. TIn. 6-aminopenicillanic acid produced. However, the combination with the 6-aminopenicillanic acid was not carried out after 3 but after 6 minutes.
Yield: 4.4 parts by weight.

IR bands at 3300, 1765, 1725, 1670, 1600, 1500-1520, 1260, 1165, 1130 cm " ¹ (Nujol).

α f (3-ethylsulfonyl-imidazolidin-2-one-l-yl) -carbonyl-aminojp-chlorophenylacetic acid:

C ₂ H ₅ -SO ₂ -N ^ i-CO-NH-CH-COOH

Cl

Le AU 038 - 51 -

309817/1174

For the suspension of 11.0 wt. Tin. p-chloro-a-ciiinophenyl acetic acid in 110 vol. tin. Sufficient concentrated sodium hydroxide solution was added to 50% aqueous Dj.oxane until the acid was just dissolved. Then dilute hydrochloric acid was added with stirring until a pH of 7.5-8.0 was reached. Now 13.0 wt. T3e. 3-Aethylsulfonyl-iniida2olidin-2-one-1-carbonyl chloride was added in portions at about ⁰ ° C. and the pE of the mixture was kept at 7.5-8.0 using dilute sodium hydroxide solution. Stirring was then continued as long as the pH was maintained from 7.5-8.0 an occasional addition of sodium hydroxide solution was still necessary. Then, at pH 6.5, most of the dioxane was removed in vacuo, about 200 vol. TIe. Added water, extracted once with ether at pH 9.0 (ether extract discarded), covered with fresh ether and brought the pH to 0.5 with stirring. The organic phase was then separated off, washed, dried and completely evaporated in vacuo. The residue was dissolved in hot ethyl acetate, then the same amount of benzene and petroleum ether was added until the cloudiness had just disappeared again and allowed to crystallize. Yield: 4.9 parts by weight.
Mp = 168 ^° C
NMR signals at T = 2.6 (4H), 4.6 (IH), 6.1 (4H), 6.3-6.7 (2H)

and 8.4-8.8 ppm (3H).

IR bands at 3300, 1720, 1650, 1540, 1350, II60 cm " ¹ (NuJoI).

Le A 14 Q? L - 52 -

9817/1174

Example 14 "" ^m

If one sets each in the manner described in Example IA

0.02 moles

D-a-R3-methylsulfonyl-imidazolidin-2-on-l-yl) -carbonyl-

aminoJ-4-chlorophenylacetic acid,

D-α - [(3-Methylsulfonyl-imidazolidin-2-on-1-yl) -carbonylaminol -4-methy! Phenylacetic acid,

D-α-1 [(3-methylsulfonyl-imidazolidin-2-one-1-yl) -carbonylaminoj-4-nitrophenylacetic acid,

D-α- [(3-Methylsulfonyl-imidazolidin-2-on-l-yl) -carbonylamino] -4-hydroxyphenylacetic acid,

D-α- [_ (3-Methylsulfonyl-imidazolidin-2-on-1-yl) -carbonylaminoj-thienyl- (2) -acetic acid,

D, L-a | (3-Methylsulfonyl-imidazolidin-2-on-1-yl) -carbonylaminoj -4-methylsulfonyl-phenylacetic acid, D-α- [(3-Aethylsilf onyl-imidazolidin-2-on-1-yl) -carbonylamino] -4-chloro-phenylacetic acid,

D-α- [(3-ethylsulfonyl-imidazolidin-2-on-1-yl) -carbonylaminoj -4-methyl-phenylacetic acid,

D-α-Γ (3-ethylsulfonyl-imidazolidin-2-on-yl) -carbonylaminol -4-nitro-phenylacetic acid,

D-α- Γ (3-ethylsulfonyl-imidazolidin-2-on-yl) -carbonyl-

aminoj-4-hydroxyphenylacetic acid,

D-α-J (3-ethylsulfonyl-imidazolidin-2-on-yl) -carbonylaminoj -thienyl- (2) -e setic acid,

D, L-a - [(3-ethylsulfonyl-imidazolidin-2-on-yl) carbonylamino] -4-methylsulfonyl-phenylacetic acid,

Le A 14 038 - 53 -

3098 1 7/1 1 7A

D-α- [(3-Acetyl-iniidazolidin-2-one-l-yl) -carbonylamino] -4-chlorophenylacetic acid -,

D-α- j (3-acetyl-imidazolidin-2-one-1-yl) - carbonylaniinoJ-4 ~ methyl! phenylacetic acid,

D-a-L (3-acetyl-imidazolidin-2-on-l-yl) -carbonylamino -4-nitro-phenylacetic acid,

D-α- jl 3-acetyl-imidazolidin-2-on-l-yl) carbonylaminoJ-4-hydroxyphenylacetic acid,

D-α- | _ (3-Acetyl-imidazolidin-2-on-l-yl) -carbonylaminoJ -4-thienyl- (2) -acetic acid,

D, L-a- Γ (3-acetyl-imidazolidin-2-on-l-yl) -carbonylaminoJ-4-methylsulfonyl-phenylacetic acid,

D-α- [_ (3-Formyl-imidazolidin-2-on-1-yl) -carbonylaminoJ-4-chlorophenylacetic acid,

D-α- [(3-formyl-imidazolidin-2-on-l-yl) -carbonylainino j -4-methyl-phenylacetic acid,

D-α- | j [3-formyl-imidazolidin-2-on-l-yl) -carbonylaminoJ -4-nitro-phenylacetic acid,

D-a- | (3-formyl-imidazolidin-2-on-l-yl) -carbonylamino] -4-hydroxyphenyl acetic acid,

D-a-r (3-formyl-imidazolidin-2-on-l-yl) -carbonylamino3-thienyl- (2) -acetic acid,

D, L-a-k3-formyl-imidazolidin-2-on-l-yl) -carbonylaminoJ -4-methylsulfonyl-phenylacetic acid,

D-α- | "(3-Furoyl- (2) -imidazolidin-2-on-1-yl) -carbonylamino] -4-chlorophenyls s igs acid,

D-α- r (3-furoyl- (2) -imidazolidin-2-on-1-yl) -carbonylaminoJ -4-methyl-phenyl acetic acid,

U AU 038 - 54 -

30981 7/1174

D-α-j_ (3-furoyl- (2) -imidazolidin-2-on-l-yl j-ear bonyiamincjj -4-nitro-phenylacetic acid, D-α- {_ (3-Furoyl- (2) -imidazolidin-2-one ~ l-yl) -carocnylaminol -4-hydroxyphenylacetic acid, D-α- | * (3-furoyl- (2) -imidazolidin-2-on-1-yl) -carbylaminoJ ~ thienyl- (2) -acetic acid, D, L-a-j_ (3-furoyl- (2) -imidazolidin-2-On-1- ^ yI) ~ carbonylaminoj -4-methylsulfonyl-phenylacetic acid » D-α-1 (3-benzoyl-imidazolidin-2 ~ on-l-yl) »carborijIaininoJ -4-chlorophenylacetic acid, D-α-r (3-Benzoyl-imidazolidin-2 ~ on-l-yl) -carbonylaminoJ -4-methyl-phenylacetic acid, D-α- r (3-Benzoyl-imidazolldin-2-on-l-yl) ~ carbonylaminoJ -4-nitro-phenylacetic acid, D-α- r (3-Benzoyl-imidazolidin-2-on-l-yl) -carbonylaminoj -4-hydroxyphenylacetic acid, D-α - [(3-Benzoyl-imidazolidin-2-on-1-yl) -carbonylarainoJthienyl- (2) -acetic acid and D, L-α-J (3-benzoyl-imidazolidin-2-on-1-yl) carbonylamino] -4-methylsulfonyl-phenylacetic acid with 0.02 mol each of tetramethylchloroformamidinium chloride and 0.022 mol of 6-aminopenicillanic acid, the following penicillins are obtained in the form of their sodium salts: D-α-j (3-methylsulfonyl-imidazolidin-2-on-l-yl) carbonylamino] -4-chlorobenzylpenicillin, D-α-j (3-methylsulfonyl-imidazolidin-2-on-1-yl) -carbonylaminoj -4-methyl-benzylpenicillin,

■ Le A 14 038 - 55 -

'0 9 S i 7/1 1 7 ι, ■■:

D-α- {_ (3-methylsulfonyl-imidazolidin-2-on-l-yl) ~ carbonyl-

aminoj-4-nitro-benzylpenicillin »

D- _a _ £ (3-methylsulfonyl-imidazolidin-2-on-l-yl) -carbony1-aminoj-4-hydroxy-benzylpenicillin,

D-α- [(3-Methylsulfonyl-imidazolidin-2-on-1-yl) -carbönylamino] -a-thienyl- (2) -methylpenicillin,

D-, L-a- [(3-methylsulfonyl-imidazolidin-2-on-1-yl) -carbony 1-amino] -4-methylsulfonyl-: benzylpenicillin,

D-α- 5 ~ (3-ethylsulfonyl-imidazplidin-2-on-1-yl; -carbonyl-

aminoj - ^ - chlorobenzylpenicillin,

D-α- [(3-ethylsulfonyl-imidazolidin-2-on-1-yl) carbonylamino] -4-methyl-benzylpenicillin,

D-α- [(3-ethylsulfonyl-imidazolidin-2-cn-1-yl) -carbonylaminoJ-4-nitro-benzylpenicillin,

D-α- [(3-ethylsulfonyl-imidazolidin-2-one-l-yl) -oarbonylaminoj ~ 4-hydroxy-benzylpenicillin,

D-α- [(3-ethylsulfonyl-imidazolidin-2-on-l-yl) carbonylamino] -a-thienyl- (2) -methylpenicillin,

D, L-a- [(3-ethylsulfonyl-imidazolidin-2-on-1-yl) carbonylamino] -4-methylsulfonyl-benzy! Penicillin,

D-α-1_ (3-acetyl-imidazolidin-2-one-1-yl) -carbonylamino J -4-chloro-benzylpenic illin,

D-α - [(3-Acetyl-imidazolidin-2-on-1-yl) -carbonylamino] -4-methyl-benzylpenicillin,

D-α-J (3-acetyl-imidazolidin-2-on-l-yl) carbonylamino] -4-nitro-benzylpenicillin,

D-α- [(3-Acetyl-imidazolidin-2-on-1-yl) -carbonylaminoI-4-

hydroxy-benzylpenicillin,

Ie AH 038 - 56 -

309817/1174

D-α- [_ (3-Acetyl-imidazolidin-2-one-l-yl) -carbonylaminoJ -α-thienyl (2) -methylpenicllline,

D, L-a - [(3-Acetyl-iaidazolid ± n-2-on-l-yl) -carbonylamInoJ-4-methylsulfonyl-benzylpenicillin,

D-α- [(3 ~ ForByl-ifflidazolidln-2-on-l-yl) -carlJonylaiBJLno] -4-chlorobenzylpenicillin,

D-α- £ (3-formyl-lialdazolidin-2-on-1-yl) carbonylamino] -4-methy1-benzy! Penicillin,

D-α- j_ (3-ForBayl-iBidazolidin-2-on-l-yl) -carbonylamino] -4-nitro-benzy! Penicillin,

D-α- [(3-Foraiyl-imidazolidin-2-on-1-yl) -carbonylaminoJ -4-hydroxy-benzylpenicillin _f

D-α- Γ (5-> Forwyl-iaiidazolidin-2-on-l-yl) -carbonylamino I -athienyl (2) -aethylpenicillin,

D, L-a- [(3-For- srl-ieidazolidin-2-on-1-yl} -carbonylamino] -4-methylsulfony ! -benzylpenicillin,

D-α- | (3-Furoyl (2) -imidazolidin-2-on-1-yl) -carbonylaminoJ-4-chloro-benzy !penicillin,

D-α- [(3-furoyl (2) -ljiidazolidin-2-on-l-yl) -carbonylaiBinoj -4-methyl-benzy! Penicillin,

D-α- \ i 3-furoyl (2) -iaidazolidin-2-on-l-yl) carbonylamino] -4-nitro-benzylpenicillin,

D-α-Γ (3-furoyl (2) -imidazolidin-2-on-l-yl) -carbonylaminol -4-hydroxy-benzylpenicillin,

D-α- [(3-furoyl (2) -imidazolidin-2-on-1-yl) -carbonylaminoJ -athienyl (2) -methy! Penicillin,

D, L-a-J_ (3-Furoyl (2) -imidazolidin-2-on-l-yl) -carbonylamino 1-4-methylsulfony1-benzylpenicillin,

Le A 14 038 - 57 -

309817/1174

D-a- [(3-Benzoyl-imidazolidin-2-on-1-yl) carbonylamino} ~ ^ -chlorobenzylpenylcillin,

D-a- [(3-Benzoyl-imidazolidin-2-on-1-yl) -carbonylamino] 4-methyl-benzylpenicillin,

D-oc-t (3-Benzoyl-imidazolidin-2-on-l-yl) -carbonylamino] 4-nitro-benzylpenicillin,

D-a- [(3-Benzoyl-imidazolidin-2-on-1-yl) -carbonylamino] A-hydroxy-benzylpenicillin,

D-α-C (3-Benzoyl-imidazolidin-2-one-1-yl) carbonylamino] α-thienyl (2) -methylpenicillin or

D-a- [(3-Benzoyl-imidazolidin-2-one-1-yl) carbonylamino] -4-methylsulfonyl-benzylpenicillin.

Le A 14 038 - 58 -

309817/1174

2152988

Example 15

If one sets in the manner described in Example IA

0.02 mole each

D-α- jCJ ^ ethylaminocarbonyl-imidazolidine - ^ - cn-l-'yl) -carbonylaminoj-phenylacetic acid, D-α Γ (3-aminocarbonyl-imidazolidin-2-on-l-yl) -carbonylaminojphenylacetic acid,

D-α Jj [3-Dimethylaminocarbonyl ~ imidazolidin-2 ~ on-l ~ yl} -carbonylaminoj-phenylacetic acid, D-α - [(3-i-Propyloxycarbonyl-imidazolidin-2-on-1-yl) -carbonylaminoj-phenylacetic acid, D-α-R 3-pyrrolid-1-yl-carbonyl-imidazolidin-2-on-1-yl) -carbonylaminoj -phenylacetic acid, D-α- [(3-piperid-l-yl-carbonyl-imidazolidin-2-one »l-y3) -carbonylaminoj -phenylacetic acid, D-α-J (3-phenylaminocarbonyl-imidazolidin-2-on-l-yl) -carbonylaminoj-phenylacetic acid, D-a - [(3-Phenoxycarbonyl-imidazolidin-2 ~ on-l ~ yl) -carbonylaminoj-phenylacetic acid,

D-a - [(3-Benzoyl-imidazolidin-2-on-l-yl) carbonylamino] phenylacetic acid,

D-α - [(3-Furoyl (2) -imidazolidin-2-on-l-yl) -carbonylamino] phenylacetic acid,

D-α - [(3-n-Butyryl-imidazolidin-2-on-l-yl) carbonylamino] phenylacetic acid,

D-α- f (2-methylsulfonylamino-4,5-dihydro-imidazol-l-yl) -

carbonylaminoj-phenylacetic acid,

Le AU 038 - 59 -

309817/1174

D-α- I (3-ethylsulfonyl-imidazolidiii-2 ~ on-1-yl) ~ carbonylaminoj-phenylacetic acid, D-α-U 3-formyl-imidazolidin-2-one-l ~ yl) carbonylamino] phenylacetic acid ,

D-α-I (3-pivaloyl-imidazolidin-2-on-l-yl) -carbonylaminolphenylacetic acid,

D-α- Γ (3-ethoxycarbonylamino-sulfonyl-imidazolidin-2-one-lyl ) -carbonylaminoJ -phenylacetic acid, D-α- Γ (3-Cyclohexyloxycarbonyl-iπlidazolidin-2-on-l-yl) -carbonylaminoj-phenylacetic acid, D-α- J ~ (3-methylsulfonyl-4-methyl-imidazolidin-2-on-1-yl) carbonylaminoj-phenylacetic acid or D-α -! (3-methylsulfonyl-5-methyl-imidazolidin-2-on-1-yl) -carbonylaminoj -phenylacetic acid with 0.02 mol each of tetramethylchloroformamidinium chloride and then with 0.022 mol of 6-aminopenicillanic acid each, the following penicillins are obtained in the form of their sodium salts:

D-α- [_ (3-methylaminocarbonyl-imidazolidin-2-one-1-yl) c arbonylamino] -benzyIpenici11in, D-α- j (3-aminocarbonyl-imidazolidin-2-on-l-yl) -carbonylaminolbenzylpenicillin,

D-α- \\ 3-Dimethylaminocarbonyl-imidazolidin-2-one-l-yl) -carbonylamino] -benzylpenicillin, D-α- [i 3-i-propyloxycarbonyl-imidazolidin-2-one-l-yl) -carbonylamino -benzylpenicillin, D-α- [(3-pyrrolid-l-yl-carbonyl-imidazolidin ~ 2-on-l-yl) -carbonylaminoj-benzylpenicillin,

Le A 14 038 - 60 -

309817 / 117-6

D-α- jj 3-Piperidid-l-yl-carbonyl-imidazolidin-2-on-l-yl) -carbonylaminoj-benzylpenicillin,

D-α- | _ (^ Phenylaminocarbonyl-imidazolidin-Z-on-l-yl) carbonylaminoj-benzylpenicillin,

D-α- [_ (3-Phenoxycarbonyl-imidazolidin-2-on-1-yl) -carbonylamino] -benzylpenicillin,

D-α-r (3-Benzoyl-imidazolidin-2-on-l-yl) -carbonylaminoJ-

benzylpenicillin,

D-α- r (3-furoyl (2) -imidazolidin-2-on-l-yl) -carbonylamino] benzylpenicillin,

D-α- [(3-Butyryl-imidazolidin-2-on-1-yl) -carbonylamino] -benzylpenicillin,

D-α- f "(2-Methylsulfonylamino-4,5-dihydro-imidazol-1-yl) -carbonylamino] -benzylpenicillin,

D-α- R 3-ethylsulfonyl-imidazolidin-2-on-1-yl) carbonylaminoj -benzylpenicillin,

D-α- L (3-Formyl-imidazolidin-2-on-1-yl) -carbonylamino | benzylpenicillin,

D-α- [(jJ-Pivaloyl-iipidazolidin ^ -on-l-yl) -carbonylaminoj benzylpenicillin,

D-α- [_ (^ Aethoxycarbonylamino-sulfonyl-imidazolidin-2-one-lyl) -carbonylaminoj -benzylpenicillin, D-α- £ (3-CyclohexyloxycaΓbonyl-imidazolidin-2-on-l-yl) -carbonylaminoj-benzylpenicillin,

D-α- [(3-Methylsulfonyl-4-methyl-imidazolidin-2-one-1-y1) -carbonylaminoj-benzylpenicillin or D-α - [(3-methylsulfonyl-5-methyl-imidazolidin-2 ~ on-1-yl) -carbonylaminoj -benzylpenicillin

Le A 14 038 - 61 -

10 9 8 17/117 /,

example

If, in the manner described in Example IA, 0.02 mol D-α- (5-benzoyl-5-methyl-biureido ^ phenylacetic acid, D-α- (5-benzoyl-5-methyl-2-thio-biureido ^ phenylacetic acid, D-α- (5-acetyl-5-methyl-biureido ^ phenylacetic acid, D-α- (! ^ Acety 1-5-methy 1-2-thio-biureido ^ phenylacetic acid, D-α- ß- (imidazolidin-2-on-l-yl-carbonyl) -ureido | -phenylacetic acid, D-α- [3- (Imidazolidin-2-on-l-yl-carbonyl) -thioureidoj-phenylacetic acid, D-α- (S-dimethylaminocarbonyl-S-methyl-biureido) -phenylacetic acid , D-α- (5-dimethylaminocarbonyl-5-methyl-2-thio-biureido) -phenylacetic acid, D-α- (5-methylsulfonyl-5-methyl-biureido) -phenylacetic acid, D-α- (5-methylsulfonyl-5-methy 1-2-thio-biureido) -phenylacetic acid , D-α- (5-methylaminocarbonyl-5-methyl-biureido) -phenylacetic acid, D-α- (5-methylaminocarbonyl-5-methyl-2-thio-biureido) -phenylacetic acid, D-α- (5-furoyl (2) -5-methyl-biureido) -phenylacetic acid, D-α- (5-furoyl (2) -5-methyl-2-thio-biureido) -phenylacetic acid, D-α- [3- (Isothiazolidin-1, l-dioxide-2-yl-carbonyl) -ureidojphenylacetic acid, D-α- 13- (Isothiazolidin-1, l-dioxide-2-yl-carbonyl) -thioureidojphenylacetic acid,

L e AH 038 - 62 -

3 0 9 8 1 7/1 1 7 U

"" 43-2152368

D-α-Pj- (pyrrolidin-2-on-1-yl-carbonyl) -ureidoj -phenylacetic acid or D-α- 3- (pyrrolidin-2-on-1-yl-carbonyl) -thioureidoj -phenylacetic acid with 0.02 mol each of tetramethylchloroformamidinium chloride and For every 0.022 mol of 6-aminopenicillanic acid, the following penicillins are obtained in the form of their sodium salts: D-α- (5-benzoyl-5-methyl-biureido ^ benzylpenicillin, D-a- (5-Benzoyl-5-methyl-2-thio-biureido) -benzylpenicillin, D-α- (5-acetyl-5-methyl-biureido) -benzy! Penicillin, D-α- (S-acetyl- ^ methyl ^ -thio-biureido) -benzylpenicillin, D-α-I3- (imidazolidin-2-on-l-yl-carbonyl) -ureidoJ-benzylpenicillin, D-α- [3- (imidazolidin-2-on-l-yl-carbonyl) ~ thioureidoj-benzylpenicillin, D-α- (5-Dimethylaminocarbonyl-5 ~ methyl-biureido) -benzylpenicillin, D-α- (5-Dimethylaminocarbonyl-5-methyl-2-thio-biureido) -benzylpenic illin, D-α- (5-methylsulfonyl-5-methyl-biureido ^ benzylpenicillin, D-α- (5-methylsulfonyl-5-methy 1-2-thio-ureido) -benzylpenicillin, D-α- (5-methylaminocarbonyl-5-methyl-biureido) -benzylpenicillin D-α- (5-methylaminocarbonyl-5-methyl-2-thio-biureido) -benzylpenicillin, D-α- (5-Furoy1 (2) -5-methyl-biureido) -benzylpenicillin, D-α- (5-furoyl (^) - 5-methyl-2-thio-biureido) -benzylpenicillin,

Le A 14 038 - 63 -

309817/1

D-a- | 3- (Isothiazolidin-l, l-dioxide-2-yl-carboiiyl) ~ ureido] benzylpenicillin,

D-a- |> -ilsothiazolidine-l, l-dioxide-2-yi-carbonyl) -thioureido] -benzylpenicillin,

D ~ a- | ~ 3 (pyrrolidin-2-on-1-yl-carbonyl) -ureidoJ-benzylpenicillin respectively.

D-α- 3- (Pyrrolidin-2-one ~ 1-y1-carbonyl) -thioureida-benzylpenicillin.

Example 17

If in the manner described in Example IA, 0.02 mol

D-α- [(3-propionyl-imidazolidin-2-on-l-yl) -carbonylamino-phenylacetic acid,

D-α- r (3-acetyl-4-methyl-imidazolidin-2-one ~ l-yl) carbonylamino] phenylacetic acid,

D-α- Γ (3-Acetyl-5-methyl-imidazolidin-2-on-l-yl) -carbonylaminoj -phenylacetic acid,

D-α- (3-acetyl-1,3-diaza-cyclohexan-2-on-1-yl) carbonylamino -phenylacetic acid,

D-a- | (3-n-Propylsulfonyl-imidazolidin-2-one-l-y ^ -carbonyl-

- phenylacetic acid,

D-α- | (3-ethylsulfonyl-4-methyl-imidazolidin-2-one-l-yIl) -carbonylamino! -Phenylacetic acid,

(3-ethylsulfonyl-5-methyl-imidazolidin-2-on-1-yl) -

carbonylaminoj-phenylacetic acid,

D-α-1_ (3-ethylsulfony 1-1,3-diazacyclohexan-2-on-l-yl) -carbonylaminoj-phenylacetic acid,

Le AH 038 - 64 -

309817/117 /.

D-α- Γ (3-methylsulfonyl-1, > -diazacy cluiiexan-2 · on-l-yl) carbonylaminoj -phenylacetic acid, D-α-j (3-n-propylsulfonyl-1,3-diazacyclohexan-2-one-l-yl) -carbonylamino] -phenylacetic acid, D-α- [_ (3-i-Propylsulfonyl-1,3-diazacyclohexan-2-on-1-yl) carbonylaminol -phenylacetic acid, D-α- [_ (3- i-Propylsulfonyl-imidazolidin-2-on-l-yl) -carbonylamino] -phenylacetic acid, D-α-j (3-i-propylsulfonyl-4-methyl-imidazolidin-2-on-1-yl) -carbonylamino -phenylacetic acid, D-α-j (3-i-propylsulfonyl-5-methyl-imidazolidin-2-one-l-yl) -carbonylamino] -phenylacetic acid, D-α-Γ (3-n-propylsulfonyl-4-methyl-imidazolidin-2-on-l-yl) carbonylamino] phenylacetic acid, D-α-R 3-n-propylsulfonyl-5-methyl-imidazolidin-2-on-l-yl) carbonylamino] phenylacetic acid, D-α- Γ (3-Phenylsulfonyl-imidazolidin-2-on-l-yl) -carbonylamino] -phenylacetic acid, D-α- Γ (3-p-methylphenylsulfonyl-imidazolidin-2-on-l-yl) -carbonylaminoj -phenylacetic acid, D-α-j (3-Cyclohexylsulfonyl-imidazolidin-2-on-1-yl) -carbonylaminoj -phenylacetic acid,

D-α- Γ (3-Thienyl (2) -sulfonyl-imidazolidin-2-on-l-yl) -carbonylaminoj -phenylacetic acid,

D-α-1 (3-Formyl-4-iaethyl-imidazolidin-2-on-1-yl) -carbonylaminoj -phenylacetic acid, D-α- Γ (3-formyl-5-methyi-imidazolidin-2-on-l-yl) -carbonylaminoj-phenylacetic acid,

Ie A 14 038 - 65 -

309817/1174

D-α- Κ 3-formyl-l, 3-diazacyclohexan-2-on-I-yl ./-carbonylaminoj-phenylacetic acid, D-α- I (3-methylaminocarbonyl-4-methyl-imidazolidin-2-on-l-yl) -carbonylaminoj-phenylacetic acid, D-α- j_ (3-methylaminocarbonyl-5-methyl-imidazolidin-2-one-l ~ yl) -carbonylaminoj -phenylacetic acid D-α- ["(3-methylaminocarbonyl-1,3-diaza-cyclohexan-2-one ~ l-yl) -carbonylaminoj-phenylacetic acid, D-α- [_ (3-methoxycarbonyl-4-methyl-imidazolidin-2-on-1-yl) carbonylaminoJ-phenylacetic acid, D-α- j_ (3-methoxycarbonyl-5-methyl-imidazolidin-2-on-l-yl) -carbonylaminoj-phenylacetic acid, D-α- i "(3-methoxycarbonyl-l, 3-diazacyclohexan-2-on-l-yl) carbonylamino] -phenylacetic acid, D-α- Γ (3-i-propyloxycarbonyl-4-methyl-imidazolidin ~ 2-on-l-yl) carbonylamino ^ -phenylacetic acid, D-α- Γ (3- i-propyloxycarbonyl-5-methyl-imidazolidin-2 ~ on-l-yl) carbonylamino] -phenylacetic acid, D-α-1_ (3-i-propyloxycarbonyl-l, 3-diazacyclohexan-2-one-l-yl) carbonylaminoj-phenylacetic acid, D-α- [(3-Methylsulfonyl-4,5-dimethyl-imidazolidin-2-on-1-yl) carbonylaminoj -phenylacetic acid, D-α- [(3-methylsulfonyl-4,4-dimethyl-imidazolidin-2-one ~ l-yl) carbonylaminoj-phenylacetic acid, D-α- [(3-methylsulfonyl-5,5-dimethyl-imidazolidin-2-on-1-yl) carbonylamino] phenylacetic acid, D-α-1 [(3-Formyl-4,5-dimethyl-imidazolidin-2-on-1-yl) -carbonylaminoj -phenylacetic acid,

Le AU 058 - 66 -

309817/1174

2152988

D-α-Ι (3-formyl-4,4-dimethvl- imidazo.iiclin-2-οϊι- 1-yl) -carbonylaminol -phenylacetic acid or D-α-Ι (3-formyl-5,5-dimethyl- imidazolidin ~ 2 ~ Qn-l ~ yl) -carbonylaminqj-phenylacetic acid- with 0.02 mol of tetramethylchloroformamidinium chloride and 0.022 mol of 6-aminopenicillanic acid each so that the following penicillins are obtained in the form of their sodium salts:

D-α-R 3-propionyl-imidazolidin ~ 2-on-l-yl) ~ carbonylamino benzylpenicillin,

D-α- ["(3 ~ acetyl-4-methyl-imidazolidin-2-on-1-yl) -carbonylaminoj-benzylpenicillin, D-α-I (3-acetyl-5-methyl-imidazolidin-2-one ~ l-yl) -carbonylaminoj -benzylpenicillin, D-α- [(3-acetyl-1,3 ~ -diaeacyclohexan-2-one-1-yTi) r-r-carbonylaminoj -benzylpenicillin, D-α- j (3-n-propylsulfonyl-imidazolidin-2-on-1-yl) -caz'bonylaminoj -benzylpenicillin, D-α-j (3-ethylsulfonyl-4-methyl-imidazolidin-2-one-1-yl) -carbonylaminoj -benzylpneicillin, D-α- [(3-ethylsulfonyl-S-methyl-imidazolidin-a-on-l-yl) -carbonylaminoj-benzylpenicillin, D-a - [_ (3-ethylsulfonyl-1,3-diazacyclohexan-2-on-1-yl) carbonylaminoj -benzylpenicillin, D-α- Γ (3-methylsulfonyl-1,3-diazacyclohexan-2-on-1-yl) carbonylaminoj -benzylpenicillin, D-α- [_ (3-n-Propylsulfonyl-1,3-diazacyclohexan-2-on-1-yl) carbonylaminoj -benzylpenicillin,

Le A 14 038 - 67 -

3 0 9 8 1 7/1 1 7 A

D-α- [_ (3-i ~ propylsulfonyl-1>> -ciiazf-oyoIohe.xan -2-one ~ l-yl) "carbonylaminoj -benzylpenicillin, D-α- (3-i-propylsulfonyl-inidazolidin ~ 2 ~ on-l-yl) -carbonylaminoj-benzylpenicillin, D-α- Γ (3-i-propylsulfonyl-4-methyl "-imidazolid.in ~ 2-on-l-yl) -carbonylaminoj-benzylpenicillin, D-α - j (3-i-propylsulfonyl-5-methyl-imidazolidine - 2-on- ~ l ~ yl) -carbonylaminoj -benzylpenicillin, D-α- j_ (3-n-propylsulfonyl-4-methyl-imidazolidine- 2-on-l ~ yl) -carbonylaminoj-benzylpenicillin, D-α- Γ (3-n-propylsulfonyl-5-iaethyl-imidazolidin-2 ~ on-l-yl) -carbonylaminoj -benzylpenicillin, D-α- ( 3-phenylsulfonyl-imidazolidin-2-one-l ~ yl) -carbonylaminoj-benzylpenicillin, D-α- R 3-p-methylphenylsulfonyl-imidazol'idin-2-on-l-yl) carbonylaminoj -benzylpenicillin, D- α- [_ (3-Cyclohexylsulfonyl-imidazolidin-2-one-l-yl) -carbonylaminoj -benzylpenicillin, Dra-L (3-thienyl (2) -sulphonyl-imidazolidin-2-on-l-yl) -carbonylaminoj -benzylpenicillin, D-α- j_ (3-formyl-4-methyl-imidazolidin-2-one-l ~ yl) carbonylaminoj-benzylpenicilli n,

D-α- r (3-formyl-5-methyl-imidazolidin ~ 2-on-l-yl) -carbonylaminoj-benzylpenicillin, D-α-I (3-formyl-1,3-diazacyclohexan-2-on-1-yl) -carbonylaminoj -benzylpenicillin,

Le AU 038 - 68 -

BATH ORIGINAL

3 0 9 8 17/117 /,

D-α- {_ (3-Methylaminocarbony.l - ^ - me thy! -Imidazo Lidin ~ 2-on-lyl) -carbonylaminoj-benzylpenicillin, D-α-1 (3-methylaminocarbonyl-5-ynethyl-imidazolidin ~ 2-on-lyl) -carbonylaminoj-benzylpenicillin, D-α- fO-methylaminocarbonyl-1,3-diazacyclohexan-2-one-lyl) -carbonylamino [benzylpenicillin, D-α- [(3-i-Propyloxycarbonyl-4-diethyl-imidazolidin-2-one-lyl) -carbonylaminoj -benzylpenicillin, D-α- R 3-i-propyloxycarbony l-5-methyl-iInida2olidin-2-one-lyl ) -carbonylaminol -benzylpenicillin, D-α-! "(3-i-propyloxycarbonyl-1,3-diazacyclohexan-2-one-lyl) -carbonylaminoj-benzylpenicillin, D-α- | ~ (3-methylsulfonyl-4,5-dimethyl-imidazolidin ~ 2-on-1-yl) ~ carbonylaminoj-benzylpenicillin, D-α- j_ (3-methylsulfonyl-4,4-dimethyl ~ imidazolidin-2-one-l-yl) -carbonylaminoj-benzylpenicillin, D-α- | _ (3-methylsulfonyl-5,5-dimethyl-imidazolidin-2-on-l-yl) -carbonylamino | -benzylpenicillin, D-α- (3-Formyl-4,5-dimethyl-imidazolidin ~ 2-on-1-yl) -carbonylaminol -benzylpenicillin, D-α-I (3-formyl-4,4-dimethyl-imidazolidin-2-on-1-yl) -carbonylamino -benzylpenicillin or D-α- | _ (3-formyl-5,5-dimethyl-imidazolidin-2-one-l ~ yl) -carbonylamino -benzylpenicillin.

D-a - [(3-methylcarbonyl-4-methyl-imidazolidin-2-on-1-yl) -carbonylaminol-benzylpenicillin, D-a - [(3-methylcarbonyl-5-methyl-imidazolidin-2-one-l ~ yl) -carbonylaminol-benzylpenicillin, D-a - [(3-methylcarbonyl-l, 3-diazacyclohexan-2-on-l-yl) carbonylamino] benzylpenicillin,

Le A 14 038 - 69 -

BATH ORIGINAL

309817/1174

Example 18

A. D, L-α- (3-Methylsulfonyl-imidazolidin-2-on-1-yl) -carbonylamino ^ -methyl-benzylpenicillin sodium:

I ₃ UU ₂ -

CH, SO ₉ -N Ü-CONH-CH-CONH-

\ j Υ CH ₃ COONa

CH ₃

This penicillin was described in Example IA

Way from 7.0 wt. TIn. D, L ~ a ~ £ (3-methylsulfonyl-imidazoli-

Din-2-on-1-yl) carbonylaminoJ -4 ~ methyl-phenylacetic acid, 3.8 wt. Tin. Tetramethylchlorformamidinium chloride and 5.0 wt. TIn. 6-aminopenicillanic acid produced.

Yield: $ 57>

ß-lactam content: 83 1 °

IR bands at 3320, 1765, 1727, 1674, 1605, 1515, 1255 and

(in NuJoI) 1170 cm "" ¹ .

NMR signals at 7 "= 2.65 (2H), 2.83 (2H), 4.3-4.6 (3H),

5.8 (IH), 6.15 (4H), 6.7 (3H), 7.7 (3H)

and 8.3-8.6 ppm (6H).

B. D, La - [(3-Methylsulfonyl-imidazolidin-2-on-l-yl) - carbonylamino] -4-methyl-phenylacetic acid:

CH ₃ SO ₂ -N N-CONH-CH-COOH

CH ₃

Le A U 038 - 70 -

30981 7/1174

This carboxylic acid was i, * der im .f e :? game IB 1 described Way from 11.3 wt. TIn. l ~ chlorocarbonyl-3-methylsulfonyl-iinidazolidone (2) and 9.1 wt. TIn. D, L-a-4- (methylphenyl) -Glycine made. Yield: 42 #

IR bands at 3700-2200, 3300, 1740-1660, 1540-1500, 1255 (in Nujöl) and 970 cm.

NMR signals at T = 1.3 (IH), 2.7 (4H), 4.7 (IH), 6.2 (4H),

6.6 (3H) and 7.7 ppm (3H).

Example 19

A. D, L-a- J "(3-Methoxycarbonyl-imidazolidin-2-on-1-yl) -carbonylaminoj-4-chlorobenzylpenicillin sodium:

-CONH-CH-CONH-j— -

CH, OCON li-CONH-CH-CONH-i-K ^, CH ₃

CH ₃ COONa

Cl

This penicillin was described in Example IA Way from 9 wt. TIn. D, L-oc- [(3-methoxycarbonyl-imidazolidine-

2-on-l-yl) carbonylaminoJ -4-chlorophenylacetic acid, 4.85 wt. Tin. Tetramethylchloroformamidinium chloride and 6.5 wt. TIn. 6-aminopenicillanic acid produced.

Yield: 80 56

ß-lactam: 85 i>

IR bands at 3300, 3050, 1770, 1742, 1730, 1670, 1605, 1520, (in NuJoI) 1320 and 1260 cm " ¹ .

Le A 14 038 - 71 -

309817/1174

NMR signals at T = 2.57 (2H), 2.65 (2H), 4.35-4.65 (3H),

6.14 (4H), 6.16 (3H) and 8.3-8.6 ppm (6H).

B. D, L-a- [_ (3-Methoxycarbonyl-imidazolidin-2-on-1-yl) -carbonylaminoj -4-chloro-phenylacetic acid:

This carboxylic acid was described in Example IB 1 Way from 10.4 wt. TIn. l-chlorocarbonyl-3-methoxycarbonyl-imidazolidone (2) and 10.2 wt. tin. D, L-a- (4-chlorophenyl) glycine manufactured. Yield: $ 61

calculated: C 47.2 H 4.0 Cl 10.0 N 11.8 found: C 47.4 H 4.5 Cl 9.2 N 11.2 IR bands at 3700-2250, 3280, 3060 and 1780- 1630 cm "" ¹ , (in Nujol)

NMR signals at T = 1.0 (IH), 2.5 (4H), 4.5 (IH), 6.15 (4H),

and 6.20 ppm (3H).

C. l-chlorocarbonyl - ^ - methoxycarbonyl-imidazolido η (2):

-N \ -C

CH ₃ OCO-N N-COCl

This carbamic acid chloride was in the manner described in Example 6B from 8 wt. TIn. N-methoxycarbonylimidazolidone-2, 9.7 wt. TIn. Trimethylchlorosilane, 9 wt. TIn. Triethylamine and 6.2 wt. TIn. Phosgene produced. Yield: 72 % mp = 129 ^° C. calculated: C 34.8 H 3.4 Cl 17.2 N 13.6 found: C 34.8 H 3.4 Cl 17.1 N 13.6

Le A 14 038 - 72 -

309817/1174

IR bands at 1820, 1737, 1690 and 1260 cm " ^1. NMR signals at = 5.7-6.3 (4H) and 6.1 ppm (3H).

D. N-methoxycarbonyl-imidazolidone-2:

CH ₃ OCO-N NH

14.9 wt. Tin. N-chlorocarbonyl-imidazolidon-2 were in 70 Vol. TIe. added ice-cold methanol and stirred at room temperature for 1 hour, then at 40-5O ⁰ C for 1 hour. After the excess methanol had been stripped off, it was recrystallized from acetone.
Yield; 55 i> m.p. = 185 ⁰ C.
Calculated: C 41.6 H 5.5 N 19.4
Found: C 41.8 H 4.8 N 19.2
IR bands at 3320, 1745 and 1670 cm " ¹ .

Example 20

A. D, L-a-K3-Methoxycarbonyl-imidazolidin-2-on-l-yl) -

carbonylaminoj -oc-thienyl (2) -methylpenicillin sodium:

CH ₃ OCO-N N-CO NH-CH-CO NH-rr ^ ^S y ^CH 3

cTy ^ CH ₃

COONa

This penicillin was described in Example IA Way from 8.5 wt. Tin. D, L-a- [O-methoxycarbonyl-imidazolidin-2-on-l-yl) -earbonylamino] -a-thienyl (2) acetic acid, 5.1 wt. Tin. Tetramethylchloroformamidinium chloride and 6.9 wt. Tin. J-aminopenicillanic acid.

Le AU 038 - 73 -

3 09817/1174

Yield: 72 #

ß-lactam content: $ 67>

IR bands at 3310, 1773, 1750, 1730, 1670, 1610, 1520, (in Nujol) 1320 and 1265 cm " ¹ .

NMR signals at T = 2.5-3.2 (3H), 4.1 (IH), 4.4-4.6 (2H),

5.8 (IH), 6.15 (TH) and 8.3-8.55 ppm (6H), According to the NMR spectrum, the crude product still contained 23% D, L-oc- [_ (3-Methoxycarbonyl-imidazolidin-2-on-1-yl) -carbonylaminoj-a-thienyl (2) -acetic acid, which, however, can be removed by fractional acidification of the aqueous solution.

B. D, L-α-f (3-methoxycarbonyl-imidazolidin-2-on-1-yl) -carbonylaminoj -oc-thienyl (2) acetic acid:

A (R, S)
CH ₃ OCO-N N-CONH-CH-COOH

This carboxylic acid was prepared in the manner described in Example IB 1 from 8.8 wt. TIn. 1-chlorocarbonyl-3-methoxycarbony1-imidazolidone) and 7.3 wt. TIn. D, La- ^ Chienyl (2) -glycine.
Yield: $ 73
Calculated: C 44.0 H 4.0 N 12.8 S 9.8 found: C 44.1 H 4.0 N 12.0 S 9.9

-2200 / _-,

IR bands at 3700 / Γ3280, 1775, 1740-1640, 1515 and 1015 cm.

(in Nujol)

NMR signals at T = 0.9 (IH), 2.5-3.1 (3H), 4.2 (IH), 6.15 (4H)

and 6.20 ppm (3H).

Le A 14 0> 8 _ 74 _

309817/1 17 / »

Example 21

D-α- [(3-ethylsulfonyl-imidazolidin-2-one-l-yl) -carbonylaminoj-benzylpenicillin-sodium:

2.9 wt. Tin was dissolved. D-α - [(3-ethylsulfonyl-imidazolidin-2-one-1-yl) -carbonylaminoJ-phenylacetic acid in 30 vol. Tin. Tetrahydrofuran, the solution was cooled to -30 ⁰ C and then was pre-cooled to -30 ^0, the C solution of 1.0 wt. Tln. Tetramethylchlorformamidinium chloride in 30 vol. Tin. Add dichloromethane all at once. Something went wrong. After the temperature to -25 ° C to -20 ⁰ C had been allowed to rise, a clear solution had formed. This solution was left to stand at -25 ° C. for 15 minutes. Then, this solution was at once to the maintained at 0 ⁰ C to 5 ⁰ C suspension or solution of 2.3 wt. Tln. 6-aminopenicillanic acid in 25 vol. TIn. 90% aqueous tetrahydrofuran, which was adjusted to pH 2.5 by adding 10% aqueous hydrochloric acid, was added. Subsequently, maintaining the pH by suitably adding 2N aqueous sodium hydroxide solution to 2.5 and cooled with an ice-water mixture, whereby the temperature was brought to 0 ⁰ C and held. After one hour, work-up was carried out, although still, if only a little, in order to maintain pH 2.5. Caustic soda had to be added. Work-up was carried out as described in Example 11.
Yield: 2.3 wt. Tin.

The IR spectrum of this penicillin was the same as that of penicillin of example 11 are identical.

Le A 14 038 - 75 -

3 0 9 8 17/1174

Claims (1)

Claims ; Penicillins of the general formula I AZ-NH-CH-CO-NH-CH CH _N , N / \ CH, CH COOH where A is a group N- NSC-N-Y-N— R ₂ R ₃ ' ^x R- -XNYN- ¹ ι ι R ₂ R ₃ R ₁ -C NYN- _R _χ_ _{Ν c} - _N _ ¹ 'IM NR ₃ R ₁ -XN C N- XNY - N- K ₂ IN U ₁ ^ 2 "x 3 R,
«_ _C ) G G represents Le A 14 038 - 76 - 3098 17/1 17 4 ϊ Μ · X is a group -S- or -C- or -C-, Q § NH Y a group -C-, -C-, -C-, NR N-aryl N-SO ₂ -R N-SO ₂ -aryl I Il H I -C-, -C-, -C- or -C-, ϊ I Z is a group -C- or -C-, Q _{1 is} a group G GGGG I I I I - (- 04-, —c — co — c-, —c— ο — c—, I 2 or 3 I I Il 6 GGGG GG GGG ' / ^{z ==} \ G II, UT i \\ /) f C-N-C-, ^ c) -C == C-, C 1 I. CN 11 o or 1 ^ O or 1 and Q _g a group GGG G GGG X -C-O — c—, -c — ν — c— Γ3 or 4 ITJJI j G GG GRG G G G GGGG ^X - C-, NfCf, —C— CO C—, TC ^ C I I 2 ι! Io or I I RG G GG G Le A 14 038 - 77 - 309817/1 174 U) or 1 ^ I ^ _{0 od # χ} , wherein R is a straight or branched chain Alkyl radical with up to 5 carbon atoms Rj_ Alkyl with up to 10 carbon atoms, cycloalkyl with up to 10 carbon atoms, alkenyl with up to 10 carbon atoms and cycloalkenyl with up to 10 carbon atoms, vinyl, ary! Vinyl, mono-, di- and trihalo-lower alkyl, H ₂ N-, R- NH-, (R) ₂ ^ N- aryl-NH-, aryl-lower alkylamino, alkoxy *) with up to 8 carbon atoms, aralkoxy ^x 'with up to 8 carbon atoms x)
Substance atoms 'cycloalkoxy' with up to 7 carbon atoms, Aryloxy ^x \ a group ROV-, RSH ₁ N-CO-V-, R-NH-CO-V-, (R) ₂ = N-CO-V-, Aryloxy ^x \ a group ROV-, RSV-, N = CV-, RO-CO-V-, R ₅ '""' ° R »N κ *, \ ß -V- ¹ N hedoutöt, ': only if X ₂ is not-S0 ₂ - at the same time. Le AH 038 - 78 - 309817/1174 V is a bivalent organic radical with 1 to 3 carbon atoms, η is an integer from 0 up to and including 2, R ^ and. R ₁ each hydrogen, alkyl and. Alkenyl with up to 8 carbon atoms each, vinyl, allyl, propenyl, cycloalkyl and cycloalkenyl with up to 6 carbon atoms each, mono-, di- and trihalo-lower alkyl, or aryl means, R ^ , R ₅ ^ and R _6- each denotes hydrogen, nitro , Nitrile, (R) ₂ ^ N-, (R) a> N-CO-, R-CO-NH-, RO-CO-, R-CO-O-, R, RO-, H ₂ N-SO ₂ -, chlorine, bromine, iodine, fluorine or trifluoromethyl, and G denotes hydrogen or R, the arrow in the divalent intermediate piece VQ ₂ - ^/ is intended to express that the linking of two atoms caused by the two free valences of this intermediate piece is not arbitrary , but should be done in the manner indicated by the arrow,
B is a group of the formula and R ₂ ,, R ^ and R _2- hydrogen, halogen, R, RO-, RS-, R-SO-, R-SO ₂ -, nitro, (R) ₈ ^ N-, R-CO-NH-, HO, R-CO-O-, where R has the meaning given above and its non-toxic, pharmaceutically acceptable salts, where the Le A U 058 - 79 - 09817/117 /, Penicillins of the general formula I and their non-toxic, pharmaceutically acceptable salts can be present in the two possible R and S configurations with regard to the chiral center C_ and as mixtures of the resulting diastereomers . 2) Compounds according to claim 1, in which the group A is CH ₃ -SQ ₂ -N (V-. 3) Compounds according to claim 1, in which the group A CH ₃ CH ₂ -SO ₂ -N (Ji- is. 4) Compounds according to claim 1, in which the group A H-CO-N (JM- is. 5) Compounds according to claim 1, in which the "group A CH ₃ CO-N (Ji- is. 6) Compounds according to claim 1, in which the group A CH ₃ OC0N (_Ji- is. 7) Compounds according to claim 1, in which the group A -OCO-N ^ JJ- is. Le AH 058 - 80 - 3 0 9 8 17/1174 8) Compounds according to claim 1, in which the group A is. 9) Compounds according to claim 1, in which the group A 10) Compounds according to claim 1, in which the group A is CH ₃ .CH-OCO-Ii, N- is. CH ₃ 11) Compounds according to claim 1, in which the group A is CH ₃ NH-CO-IfSi- '. 12) Compounds according to claim 1, in which the group A H ₂ NCO-I (JN- is. 13) Compounds according to claim 1, in which B is phenyl. 14) Compounds according to claim 1, in which B is p-nitrophenyl. 15) Compounds according to claim 1, in which B is p-Methy! Phenyl. Le AU 038 - 81 - 309817 / 1m 16) Compounds according to claim 1, in which B is p-chlorophenyl. 17) Compounds according to claim 1, in which B CHs-CO-NH- ^ ¹ ^ - is. 18) Compounds according to claim 1, in which B is p-hydroxyphenyl. 19) compounds according to claim 1, in which B Is CH _{3 -SO 2} - ^ ~ Λ-. 20) Compounds according to claim 1, in which B is thienyl (2). -JL 21) Compounds according to claim 1, in which C is in the R configuration. 22) D-α- [(3-methylsulfonyl-imidazolidin-2-one-1-y1) ■ carbonyl-aminoj -benzylpenicillin. • i (R) CH ₃ -SO ₂ -N ^ T-CONH-CH-CONH COOH Le A 14 038 - 82 - 3 09817/1174 23) L-α - [_ (3-Methylsulfonyl-imidazolidin-2-on-1-yl) -carbonylaminoj -benzylpenicillin. CH ₃ SO ₂ - ίΐΊ ^ Ii ^ i COOH 24) α-f (3-methylsulfonyl-imidazolidin-2-on-1-yl) carbonylaminoj-4-chlorobenzylpenicillin. CH ₃ SO ₂ -N; "N-CONH-CH-CONH-r- ^ _v , CH CH ₃ COOH " Cl 25) a- [(3-Methylsulfonyl-imidazolidin-2-on-1-yl) -carbonylaminoj-a-thienyl (2) -methy! Penicillin, CH ₃ Sun ₂ - CH ₃ COOH 26) α- Κ3-methylsulfonyl-imidazolidin-2 ~ on-1-yl) carbonylaminoj -2, e-dichloro-benzylpenicillin. -N _x ^ - CH ₃ SO ₂ - COOH Le AU 058 - 83 - 30981 7/1174 27) D-OC- [J3-Acetyl-imidazolidin-2-on-1-yl) -carbonylaminoj -benzylpenicillin. Q (R) CH ₃ -CON ^ N-CONH-CH-CONHt-r ^ v CH, H ₃ COOH 28) L-a-ß3-acetyl-imidazolidin-2-one-l-yl) -carbonylaminol-benzylpenicillin. 0 (S) CH ₃ CO-N ^ JI-CONH-CH-CONH- ^ cooH 29) a- [_ (3-Acetyl-imidazolidin-2-on-1-yl) -carbonylaminoJ-A-chlorobenzylpenicillin. CH ₃ CO-N ^ JJ-CONH-CH-CONH- COOH Cl 30) a- 1_ (3-Acetyl-imidazolidin-2-on-l-yl) -carbonylaminoj 4-methyl-benzyl penicillin. -IiN- CH, ¹ Xj ^ COOH CH ₃
Le A 14 038 - 84 - 3 0 9 8 1 7/1 1 7 31) α- [_ (3-Acetyl-imidazolidin-2-one-l-yl) - carbonylamine qj-α-thienyl (2) -methy! penicillin. CH ₃ CON ^ N-CONH-CH-CONH-r-v ^ CH ₃ CH ₃ COOH 32) a - [_ (3-Acety; i ^ im ± daz © lidin-2-on-l-yl) - carbonylaminoj- 2, e ^ dichlorobenzylpenicillin. CH ₃ CO-I ^ Ji-CONH-CH-CONH- COOH 33) D-α- f (3-ethylsulfonyl-imldazolidin-2-on-l-yl)? carbonylaminoj -benzylpenicillin. (R) . ■ CH ₃ CH ₂ SO ₂ - COOH 34) a- | _ (3-Aethylsulfonyl-imidazolidin-2-on-l-yl) carbonylaminoj -4-chlorobenzylpenicillin. 0 CH ₃ CH ₂ SO ₂ - J COOH Cl Le A 14 038 - 85 - 30981 7/1174 35) D-α- [_ (3-Formyl-imidazolidin-2-one-1-yl) carbonylaminoj -benzylpenicillin. Q (R) H-CO-N N-CONH-CH-CONH- COOH 36) LT-a-j_ (3 ~ formyl-imidazolidin-2-on-1-yl) -carbonylaminoj-benzylpenicillin. i is) HCO-N N-CONH-CH-CONH --—- ^ ' ³ CH ₃ COOH 37) a- [(3-Formyl-imidazolidin-2-on-1-yl) -carbonylaminoj-4-Cjilor-benzylpenicillin. HCO-N ^ -CONH-CH-CONH-TTr ² V ^CH 3 N COOH Cl 38) a-J_ (3-Formyl-imidazolidin-2-one-1-yl) carbonylaminol-4-methy! -Benzylpenicillin. -ιφ-c hco-n: n-conh-ch-conh- COOH CH ₃ Le AU 038 - 86 - 3098 17/1174 39) α-1 [(3-Formyl-imidazolidin-2-one-1-yl) carbonylaminoj-α-thienyl (2) -methy! Penicillin. -N Ji- HCO- ^ Cr COOH 40) D-α- [(3-Methylsulfonyl-imidazolidin-2-on-1-yl) -carbonylaminoj -2.5-di] O (R) CH ₃ SO ₂ -N ^ Ji-CONH-CH-CONHj- ^ y < COOH 41) D-α -! _ (3-formyl-imidazolidin-2-on-l-yl) - carbonylaminoj-2,5-d.ihydro-benzylpenicillin HCO-A-CONH COOH 42) a- [(3-Methylsulfonyl-imidazolidin-2-on-l-yl) carbonylaminoJ-4-methyl-benzylpenicillin. CH ₃ SO ₂ - _ Il COOH CH ₃ Le A M 038 - 8? - 309817/1174 43) α- | _ (3-Methoxycarbonyl-imidazolidin-2-on-1-yl) -carbonylaminoj -4-chloro-benzylpenicillin. CH ₃ N ^ jYy COOH 44) a - [_ (3-Methoxycarbonyl-imidazolidin-2-one ~ l-yl) carbonylaminoj-α-thienyl (2) -methy! penicillin CH, ^ f W * COOH 45) Use of the penicillins according to claims 1-44 as antibacterial agents. 46) Use of the penicillins according to claims 1-44 as medicaments in the Buaanaedisln. 47) Araneialttel, characterized by a content of peni cillins according to claims 1-44. 46) Process for establishing connections between the general TormeL I: A-Z-NH-CH-Cc-Nh-Jn - CH \ I I! where A, Z, B and C have the meanings given above, • I characterized in that G-aminopenicilie-n-acid le A 1 4 038 - 88 - 309817/1 174 (Formula II) or compounds of the general formulas III or IV H ₁ N-CH CH I J. .Κ CH ₃ OOH CH CO "." - CH-df \ ^ CH, ι ι ^x ~ ^ I ^ 1 CO-O-Si-R ₁ R _{1 Λ} -Z ^ Si-NH-CH CH \ ^ CH _{3 Iy} I c-N / N: h ₃ XH CO-O-Si ^ - in which R ₁₀ , R ₁₁ and R _1t each denote alkyl with up to 6 carbon atoms , with carboxylic acids of the general formula V modified at the carboxyl group A-Z-NH-CH-COOK V E where A, Z, B and C have the abovementioned tiedeutun _u en, in the case of the use of 6-aminopenicillic acid in .vasser- Z * 4 U S38 - 89 - 309817/1174 free or water-containing solvents in the presence of a base, in the case of use of the compounds of the general formulas III or IV, in anhydrous and hydroxyl-free solvent, with or without addition of a base at a temperature in the range of about -70 ⁰ C to +50 ⁰ C, preferably at -5O ⁰ C to O ⁰ C to implement. 49) Method according to claim 4.8, characterized in that when using 6-aminopenicillanic acid in one water-containing solvents the reaction with the at the ™ carboxyl modified carboxylic acids V in a pH range of about 2-9, preferably in the pH ranges of from about 2-3 or from 6.5 to 8.5 executes. 50) Process according to claim 48 and 49, characterized in that in the preparation of the carboxylic acids V modified at the carboxyl group, these carboxylic acids, their salts of the general formula Va or their silyl esters of the general formula Vb or Vc A-Z-NH-CH-COOH [AZ-NH-CH-COO ^ ') Me ^iiV ^ ^y Va / 10
AZ-IVh-CH-CO-O-Si-R ₁₁ Vb ι ^ JI Le A 14 038 - 90 - 3098 17 / 117-4 A-Z-NH-CH-CO-O. > R A-Z-NH-CH-CO-O Si N ₁₁ Vc wherein A, Z, B ₁ R ₁₀ , R ₁₁ , R ₁₁ and C * have the meanings given above and Me ¹¹ ^ ⁺ 'stands for a cation of the alkali or alkaline earth metals, or for a cation of the element aluminum and'η each one is an integer from 1 to 3, used as starting compounds. 51) Process according to Claim 48, 49 and 50, characterized in that the carboxylic acids of the general formula V, or their salts Va, or their silyl esters Vb or Vc, are converted into carboxylic acids of the general formula V modified at the carboxyl group by converting they with about one molar equivalent of the compounds of the general formulas VI, VII, VIII or IX THERE VI VII Κ Α 14 033 30S81 7 ■ CH ₂ -CH ₂ y -K _13th VIII —W -H ¥ ^v IX where R has the meaning given above, R ₁₃ either has the same meaning as R or phenyl, R _{14 is} a divalent organic radical - (CH ₂ ) ₄ -, - (CH ₂ ) ₅ - or - (CH ₂ ) ₂ - 0- (CH _a ) ₂ -represented and W is halogen, if the compounds V or Va are used in a water-containing or anhydrous organic solvent, if the compounds Vb or Vc are used in an anhydrous and hydroxyl-free, inert organic solvent, in the presence or absence of a base at -7O ⁰ C to + 3O ⁰ C, preferably at -50 ⁰ C to 0 ⁰ C to implement. 52) Method according to claim 48, 49, 50 and 51, characterized in that that the reaction of the carboxylic acids of the general formula V, their salts Va or their silyl esters Vb or Vc with the compounds of the general formulas VI, VlI, VIII or IX in the presence of about one molar equivalent of the N-hydroxy compounds the general or special formulas Le A 14 038 - 92 - 3 0 9 8 1 7/1 1 7 U X, Xa or Xb: HO-N = C HO-NT Κί? Xa Oh wherein U is the radical -C = N and / or -COON lower alkyl, undertakes. 53) Process according to claim 4.8, 49 and 50 "characterized in that the carboxylic acids of the general formula V, their salts Va or their silyl esters Vb or Vc are converted into carboxylic acids of the general formula V modified at the carboxyl group by converting them with about a molar equivalent _Λ 1 of the compounds of the general formulas XI or XIa or half a to one molar equivalent of the compounds of the general formulas XlI or XlIa: XI, -C = Ν <' ¹ⁱ XlI »W Κι j L # AU 038 - 93 - 3098 17/1174 W-CH = NR ₁₄ XIa, ^> C = NR ₁₄ XIIa in which W, R _tJ and R _{14 have} the meanings given above, in the case of using the compounds of the general formulas XI or XIa in the presence of about one molar equivalents, in the case of using the compounds of the general formulas XII or XIIa in the presence of half to one molar equivalent of the N-hydroxy compounds X, Xa or Xb, in the case of using the compounds V or Va in an aqueous or anhydrous organic solvent, in the case of the use of the compounds Vb or Vc in an anhydrous and hydroxyl-free, inert organic solvent, in , preferably brings the presence or absence of a Ease at -70 ^e C to + 3O ⁰ C at -50 ° C to O ^e C for reaction. 54) Method according to claim 48, 49, 51 and 53, thereby cool indicates that an optical activity present at the chirality center C is preserved from possible racemization by the fact that no or relatively weak carboxylic acids V, or their salts Va, or their allyl esters Vb or Vc, are converted into the carboxylic acids V modified at the carboxyl group organic bases, for example N-methyl- «orpholJla, H-ethylmorpholine, Μ, Η-dimethylaniline, pyridine or inorganic bases or buffer mixtures are used. U A 14 056 - 94 - 309817/1174 55) The method of claim 48 and 54, characterized in that by converting the carboxylic acids of the general-Formal V in modified at the carboxyl group Carbonsäureη that compounds of the general formula X wherein U has the meaning given above in an anhydrous, inert organic solvent in the presence of at least one molar equivalent of an organic base which serves as an acid acceptor, at temperatures of about -40 ⁰ C to +25 ⁰ C with a mol- i equivalent of thionyl chloride to form one molar equivalent of base hydrochloride in unknown intermediate compounds and these without isolation in the presence of a further molar equivalent of a base with one molar equivalent of the carboxylic acids of the general formula V or without the addition of a base or with up to one molar equivalent of a base with one molar equivalent the compounds of general formulas Va, Yb or Vc brings at a temperature of about -40 ⁰ C to +30 ⁰ C for reaction, wherein said group at the carboxyl * altered carboxylic acids V of the general formula XIII: A-Z-NH-CH-C '/ U I "0-N = C ^ XIJ B ^ U in the A, Z, B, C * and U the above -.geb ^ ne can be obtained. Le A 14 BATH ORIGINAL 309817/11 7A 56) Process according to claim 48, characterized in that the carboxylic acids of the general formula V are thereby in an the carboxyl group changed carboxylic acids of the general formula XIII converted that they are in the presence of about one molar equivalent of the compounds of the general formula X with about one molar equivalent of a carbodiimide in one Diluent - in the case of the subsequent use of the compounds of the general formulas III and IV in one brings anhydrous and hydroxyl-free diluents to the implementation. Le A 14 038 30981 7/1 1 7A