DD201598A5 - PROCESS FOR PREPARING NEW BETA-LACTAME - Google Patents

Abstract

Described are new * -lactams of general formula I wherein R & ind1! an aliphatic acyl or alkoxycarbonyl group or the aminocarbonyl group and X represents the groups, wherein D is a hydrogen atom, an acetoxy, aminocarbonyloxy, pyridium or 4-aminocarbonyl-pyridinium group or a group -SHet (Het is for example the 1-methyl-tetrazole -5-ylrest); and E represents a hydrogen atom or an in vitro or in vivo readily cleavable protecting group, and R represents a hydrogen atom, the cyclopropyl group, a lower hydroxyalkylamino group, an amino, alkyl or alkenylamino group, a cycloalkylamino group or a group of the general Formula II means where n is the numbers 0 or 1 and R & ind3! and R & ind4! Represent hydrogen, hydroxy, acetylamino, aminocarbonylamino, nitro, aminocarbonyl, cyano, methylsulfinyl, methylsulfonyl, aminosulfonyl or methylaminosulfonyl groups. It further describes their salts with inorganic or organic bases, 3 processes for the preparation of these compounds and medicaments containing these compounds. The compounds of general formula I act against both gram-positive and especially against gram-negative bacteria and bacteria-like microorganisms; the compounds are characterized by a strong action and a broad spectrum of action. Formula I, II u. groups

Description

2319 66 7

^; Berlin, 16.11.1981

AP C 07 D / 231 966/1 (59 336 12)

Process for the preparation of novel β-lactams Field of application of the invention

The invention relates to production process of new ß-lactams, which act against both Gram-positive and against Gram-negative bacteria and have a very broad spectrum of activity. They can be used in medicine as a remedy.

Well-known technical solutions

There are already Hydroxypyridylureidobenzyl penicillins of the general formula

E-CH-GOHH

OH

CO NH

COOH

(M-OS 2,535,655, 2,450,668, US Pat. No. 4,031,230), but their action against Gram-negative bacteria was unsatisfactory.

The same applies to those compounds which the ^G roup -NH-CO- comprise instead of the group -NH-CO-NH-, -flobei with the CO group, a pyrimidine ring is linked (BE-FS 828 933, DE-OS 2 34 -7,533).

2319 66 7 3 *

16/11/1981

AP C 07 D / 231 966/1

£ 59,336 12)

The most effective ureidopenicillin is the piperacillin with the group

- NH - CG - NH - N

N - C ₂ H ₅ ,

which showed only mediocre effects against a number of germs,

Object of the invention:

It is an object of the invention to achieve an increase in activity over the known structurally comparable compounds.

Essence of the invention

The invention has for its object to provide processes for the preparation of new ß-lactams ..

In accordance with the invention, new β-lactams of the general formula I are prepared

(D,

if appropriate, their physiologically tolerated salts with inorganic or organic bases, process for the preparation of the compounds and these compounds containing «

231 9 66 T

In the general formula I mean:

R is an aliphatic acyl or alkoxycarbonyl group having 2 to 5 carbon atoms or the aminocarbonyl group,

X the groups

/ --CH ₃ »* ^ C-Oy ,,

0OE COOE

wherein

D is a hydrogen atom, an acetoxy, ^{aminocarbonyloxy,:]} pyridinium or 4-aminocarbonyl pyridinium or '. \ Group -SHet, wherein Het is the i-methyl-tetrazole-5-:; yl, 1,2,4-thiadiazol-S-yl / 3-methyl-1,2,4-thiadiazole-5

yl, 1,3,4-thiadiazol-2-yl, 2-methyl-1,3,4-thiadiazol-5- \ yl or the 4-methyl-5,6-dioxo-1,2,4 represents -triazin-3-yl group and

E is a hydrogen atom or an in vitro or in vivo easily; cleavable protecting group; i

'-. R is a hydrogen atom, the cyclopropyl group, the 2'-hydroxyethylamine, the 3'-hydroxypropylamino or the 4'-hydroxycyclohexylamino group or a group of the general formula

; - N ', where R- is hydrogen, a \

branched or unbranched alkyl or alkenyl group having 1 to 4 carbon atoms or a cycloalkyl radical having 3 to 6 carbon atoms,

2319 66 ^{7? "}

R is further a group of the general formula

-HH (CH,) η _ / ^ S ⁴

wherein η - ο or 1 and R and R, which may be identical or different, are hydrogen atoms, the hydroxy, acetylamino, aminocarbonylamino, nitro, aminocarbonyl, cyano, methylsulf inyl, methylsulfonyl, aminosulfonyl or the methylaminosulfonyl group.

Within the meaning of the invention, suitable carboxyl protective groups E are those which have hitherto been used in the field of penicillins and cephalosporins, in particular ester-forming groups which can be removed by hydrogenolysis or hydrolysis or other treatments under mild conditions, or ester-forming groups can be easily split off in the living organism. Examples of in vitro readily cleavable protecting groups are e.g. the benzyl, diphenylmethyl, trityl, t-butyl, the 2,2,2-trichloroethyl or the trimethylsilyl group.

E represents hydrogen, so fall well as pharmaceutically acceptable salts such as alkali metal or alkaline earth metal under the ^claim: salts such as sodium, potassium, magnesium or calcium salts, ammonium salts, organic amine salts, for example with triethylamine or dicyclohexylamine.

If D is pyridinium or aminocarbonylpyridinium, then the compounds of the invention have the general formula Ia

2 319 6 6 7

(Ia)

N V- (CONH ₀ )

W / ²

where m is the number O or 1.

Preference is given to those compounds of the general formula I in which

R. represents a methoxycarbonyl, ethoxycarbonyl, acetyl or aminocarbonyl group,

X is as defined above and in XE is a hydrogen atom and

D represents a hydrogen atom, the acetoxy group or the group: SHet, wherein Het is the i-methyltetrazol-5-yl,: the 1,3,4-thiadiazol-S-yl or the 2-methyl-1,3,4 -thia- _: diazol-5-yl group; and

R has the meanings given above.

A particularly preferred embodiment of the invention is where R is the group of the general formula

-NH-

stands,

231966 7

-JSf-

wherein

_{R 3,} hydroxy, methylsulfinyl, methylsulfonyl, aminocarbonyl, aminocarbonylamino, aminosulphonyl or methyl

Aminosulfonyl group means! or that R is the

 m-hydroxy-p-aminosulfonylanilino, cyclopropyl, propylamino,

ilsopropylamino, cyclopentylamino, cyclohexylamino, 3'-hydroxy-propylamino, 4'-hydroxycyclohexylamino group, R ₁ and X are as defined above.

The β-lactams of general formula I can exist in two tautomeric forms (namely lactim and lactate type). It depends particularly on the particular solvent and on the nature of the substituent R, which predominates of the two forms I- or I ¹ :

^H i ° _Avs

C ^- H-CONH

NH

2 319 6 6 7

It goes without saying that the compounds of general formula I given above always include both tautomers.

 The compounds of general formula I can be described with reference to

center of chirality C + in the two possible R and S confirgations, but also as a mixture of these two configurations. Particularly preferred are those compounds for which the D = R configuration is true. When the end product is obtained in the D, L form, the pure D- and L-diastereomers can be prepared by preparative liquid chromatography. ι (HPCL) produce.

The compounds of general formula (I) can be prepared as follows:

1. Compounds of the general formula I, in which D has the meaning indicated except that of a pyridinium or aminocarbonylpyridinium group, by reacting a compound of the general formula

(II)

in which R ₁ and X have the abovementioned meaning and D have the abovementioned meaning with the exception of a pyridinium or aminocarbonylpyridinium group, with a pyrimidine derivative of the general formula

(III)

2319667

wherein R is as defined above and B is the group -NCO or a reactive derivative of the group -NHCOOH, e.g.

the groups -NHCOCl, -NHCOBr or -NH-COO- ^ / ^NC V

wherein the groups -NCO and -NHCOCl are particularly preferred. It is also possible to use mixtures of such pyrimidine derivatives of the general formula III, in which B has partly the one and partly the other of the abovementioned meanings, e.g. the groups -NCO and -N-COCl simultaneously side by side. H

If E is a hydrogen atom, the starting materials of general formula II can be used in the form of their inorganic or organic salts, for example as triethylammonium salt or sodium salt. The reaction can then be in any mixtures of water with such organic solvents which are miscible with water, such as ketones, for example acetone, cyclic ethers, for example tetrahydrofuran or dioxane, nitriles, for example acetonitrile, formamides, for example dimethylformamide, dimethyl sulfoxide or alcohols such as isopropanol or be carried out in hexametapol. The pH of the reaction mixture is maintained by addition of bases or use of buffer solutions in a pH range of about 2.0 to 9.0, preferably between pH 6.5 and 8.0. However, it is also possible for the reaction in anhydrous organic solvents, for example halogenated hydrocarbons such as chloroform or _methylene: lenchlorid perform the addition of bases, preferably triethylamine, diethylamine or N-ethylpiperidine. Furthermore, the reaction can be in a mixture of water and a water-immiscible solvent such as ether, eg 'diethyl ether, halogenated hydrocarbons, eg chloroform or methylene chloride, carbon disulfide, ketones, for example isobutyl methyl ketone, esters, eg ethyl acetate, aromatic solvents , For example, perform benzene, where it is appropriate to stir vigorously, and the pH by

2319 66 7

Base addition or use of buffer solutions in a range of about pH 2.0 to 9.0, preferably between 6.5 and 8.0. However, the reaction can also be carried out in water alone in the presence of an organic or inorganic base or with the addition of buffer substances.

If E denotes the trimethylsilyl group, the starting materials used for the process according to the invention are the silyl derivatives of the compounds of the general formula II (for example mono- or advantageously the di-trimethylsilyl derivatives silylated at the amino and carboxyl groups) and reacted with compounds of the general formula III , so -man generally works expediently in water and hydroxyl group-free solvents, for example in halogenated hydrocarbons, z.3. Methylene chloride or, chloroform, benzene, tetrahydrofuran, acetone or dimethylformamide, etc. The addition of bases is not necessary here, but may be advantageous in individual cases, to improve the yield and purity of the products. As optionally added bases suitably tertiary aliphatic or aromatic amines such as pyridine or triethylamine, or by steric hindrance difficult acylatable _: secondary amine such as dicyclohexylamine, used. Means E; one of the other above mentioned in vitro or in vivo easily cleavable protecting groups, for example the Diphenylmethylestergruppe or Pivaloyloxymethylgruppe, so it is also advisable. if working in an aprotic solvent, for example in absolute methylene chloride, chloroform, tetrahydrofuran or dimethylformamide.

The amount of bases used is e.g. determined by the desired maintenance of a specific pH. Where a pH measurement and adjustment is not made or is not possible or useful because of the lack of sufficient amounts of water in the diluent, in the case of using the non-silylated compounds, the general formula

2319 66 7

mel II preferably used 1.0 to 2.0 molar equivalents of bases. In the case of using the silylated compounds, it is preferred to use up to one molar equivalent of base.

As bases, in principle, all organic and inorganic bases commonly used in organic chemistry can be used, such as alkali and alkaline earth hydroxides, alkaline earth oxides, alkali and alkaline earth carbonates and bicarbonates, ammonia, primary, secondary and tertiary aliphatic and aromatic amines and heterocyclic bases. Examples are sodium, potassium and CaIziumhydroxid, calcium oxide, sodium carbonate and potassium carbonate, sodium and potassium: bicarbonate, diethylamine, methyl-ethylamine, ^triethyl-: called piperidine: amine, hydroxyethylamine, aniline, dimethylaniline, pyridine and the like. When using the silylated starting materials, however, the abovementioned restrictions regarding the nature of the bases should be taken into account.

As buffer systems, all common buffer mixtures may be used, e.g. Phosphate buffer, citrate buffer and tris (hydroxymethyl) amino methane buffer.

; The reaction temperatures can be in a wider range. be varied. In general, one works between -20 and +50 C, preferably between 0 and +20 C.

The reactants of the general formulas II and III can be reacted with each other from the outset in equimolar amounts. But it can in some cases' well be expedient to use one of the two reactants in excess, in order to facilitate the cleaning of the final product or to increase the yield.

2. Compounds of the general formula I, in which D has the meanings given above, with the exception of a pyridinium or aminocarbonylpyridinium group, by reacting ureidocarboxylic acids of the general formula IV,

2

I-COOH

(IV)

OH

in which R and R have the abovementioned meanings, their salts or reactive derivatives, with compounds of the general formula V,

in the X, the meanings given above, with the exception of the formula in which D is pyridinium or aminocarbonylpyridxnium,

2 319 6 6 7

As reactive derivatives of ureidocarboxylic acids of the general!

Formula IV includes, for example, their acid anhydrides, e.g. i

those derived from chloroformates, e.g. Chlorameisen- säureäthyl- or isobutyl ester, derived, or their reactive J

Esters, such as the p-nitrophenyl ester or the N-hydroxysuccin; imidester, or their reactive amides, such as the N-carbonylimidazole / but also their acid halides, such as the corresponding acid chloride or their acid azides in question.

In principle, however, all the linking methods known from β-lactam chemistry can be used.

The 7-Aminocephalosporansäure- or Penicillansäurederivate the general formula V are advantageously used in the form of an in vitro or in vivo readily cleavable derivative. For this purpose, for example, the compounds of general formula V come into question, in which Ξ has the meanings given at the outset with the exception of a hydrogen atom; Particularly preferred derivatives are the Diphenylmethy _esters: the t-butyl ester, the trimethylsilyl ester or Ν, _Ο-bis-: trimethylsilyl.

For example, the ureidocarbonsäuren, their salts or their reactive derivatives with the 7-aminocephalosporan or 6-Aminopenicillansäurederivaten in a solvent at temperatures between -40 C and +40 C, optionally in the presence of a base, implemented. If, for example, an anhydride of the ureidocarboxylic acid, for example the anhydride with the Äthylchloroformiat used, the reaction is carried out under cooling, for example at -40 ° C to +10 ⁰ C in a solvent such as acetone, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane, hexametapol or in a mixture of these solvents. If, for example, an N-hydroxy-succinimide ester of the ureidocarboxylic acid is reacted with derivatives of the general formula V, the reaction is preferably carried out at 0 to 20 ° C. in the presence of a base, for example triethylamine, in a solvent such as dimethylformamide, di-

231966 7

chloromethane, dioxane or in a mixture of such solvents

·

: tel performed. \

! The reaction of a ureidocarboxylic acid of general formula IV itself or its salts with compounds of the general

Formula V is advantageously carried out in the presence of a _; Condensing agent, for example in the presence of N, N'-dicyclohexylcarbodiimid.

3. cephalosporin derivatives of general formula I in which D is the '-. Has meanings of an -S-Het, pyridinium or 4-aminocarbonylpyridinium group, by reacting a compound

the general formula VI,

CH ₂ OCOCH ₃

(VI)

COOH

in the ·

R ₁ and R have the meanings given above, either with a compound of general formula VII,

Het - S - M

(VII)

in the

Het has the meanings given above and M is a hydrogen atom or an alkali metal or an alkaline earth metal or with pyridine or 4-aminocarbonylpyridine. For this purpose, e.g. a compound of the formula VI with, for example, 5-methyl-2-mercapto-1,3,4-thiadiazole in a solvent,

2319 66 7 -ΊΡ

such as. Water, methanol, ethanol, acetone, methyl ethyl ketone, tetrahydrofuran, acetonitrile, ethyl acetate, dimethoxyethane, dimethylformamide, dimethyl sulfoxide, chloroform or a mixture of these solvents. It is preferable to use a strong polar solvent such as water, acetonitrile or the like. In the case of water as a solvent, the pH of the reaction solution is advantageously maintained at 2 to 10, more preferably 4 to 8. The desired pH can be adjusted by adding a buffer solution, such as sodium phosphate. The reaction conditions are not particularly limited. Normally, the reaction is carried out at a temperature in the range of 0 to 100 seconds.

rich from 0 to 100 C for a period of some

The compounds according to the invention prepared by methods 1-3, in which E is an easily separable in vitro protecting group, körinen be converted by known methods of cephalosporin or Penicillinchemie in the free carboxylic acids (E = hydrogen) of the general formula I. For example, the trimethylsilyl group can be readily removed by aqueous hydrolysis or the diphenylmethyl ester group e.g. by hydrolytic cleavage with trifluoroacetic acid. This elimination of the protecting groups is well known.

Likewise, the antibiotics of formula I or I ¹ , wherein E is a hydrogen atom, in Acyloxyalkylester, wherein E, for example, a pivaloyloxymethyl radical

- CH 1 -OC-C (CH) O

means, by reacting an alkali salt of the free carboxylic acid, for example a sodium or potassium salt, with a Pivaloyloxymethy! halide of the formula

231966 7

Hal-CH ₀ -OCC (CH,) _

where Hal is chlorine, bromine or iodine. Further suitable acyloxyalkyl halides are 2.B. Chloromethyl acetate, bromomethyl propionate or 1-bromoethyl acetate.

The preparation of the acyloxyalkyl esters of the formula I is carried out by reacting the respective alkali metal salt of the parent acid in an inert solvent. a slight molar excess of the iodo, bromo or chloroalkyl esters, such as pivaloyloxymethyl iodide, at room temperature or slightly elevated temperature up to about 40 to 4 5 ° C. As the solvent, for example, acetone, tetrahydrofuran, dioxane, dimethylformamide or methylene chloride can be used.

The work-up of the reaction mixtures obtained by the said processes after the reaction is carried out according to the methods customary in β-lactam antibiotics; the same applies to the isolation and purification of the end products, for example for the release of the acid or its conversion into other salts by means of inorganic or organic bases. For the preparation of the potassium or sodium salts _, the precipitation of these salts is particularly advantageous _; an alcoholic-ethereal solution of the free acid by: the addition of potassium or sodium 2-ethylhexanoate or _: reaction of the free acid with the appropriate amount of sodium bicarbonate under pH control and.Kühlung and subsequent freeze-drying.

The starting materials of the formula II are known or can be in; Analogy to known substances according to known methods! prepared, for example by acylation of the known Aminolactame of formula IV and, if desired, subsequent; Reaction of cephalosporanic acid derivatives of the formula: II (D = -OCOCH ₃ ) thus obtained with thiols of the formula Het-SH.

2 319 6 6 7 - ψ-

The starting materials of the general formula III can be prepared, for example, by reacting the corresponding 5-aminopyrimidines of the general formula VIII,

Qr ^0H

in the

R is as defined above, be obtained with phosgene. This reaction is preferably carried out in a non-hydroxyl-containing solvent, such as tetrahydrofuran, methylene chloride, chloroform, dimethoxyethane or hexametapol at temperatures between -40 ° and + 60 ° C, preferably between -10 ° and +20 ⁰ C. It is recommended that the Hydrogen chloride formed by equimolar amounts of an inert organic base such as triethylamine or pyridine to bind. As a solvent, pyridine can also be used in excess. If the relevant aminopyrimidines of the general formula VIII are sparingly soluble in one of the solvents mentioned, the phosgenation can also be carried out in a heterogeneous phase. Furthermore, the aminopyrimidines of general formula VIII can be prepared by treatment with a silylating agent, such as hexamethyldisilazane or trimethylchlorosilane / triethylamine, trimethylsilyldiäthylamin or N, 0-Bistrimethylsilylacetamid in a generally very readily soluble in the solvents mentioned, simple or, according to the existing exchangeable hydrogen atoms,

2 319 6 6 7 '~ -% ~

repeatedly silylated aminopyrimidine are converted, which then reacts with phosgene to form the corresponding compounds of general formula III. Depending on the type of solvent, the amount of temperature, the amount and type of base used either predominantly the corresponding isocyanate or Carbaminsäurehalogenid or a mixture of these two compounds. Depending on the reaction conditions, the compound of general formula III may also be partially or ^; entirely as isocyanate-dihydrooxazolo-pyrimidine of general formula IIIa,

ι (III *)

or in the case of previous silylation, depending on the nature of the substituent R, as mono- or polysilylated analog.

The resulting by phosgenation starting materials of general formula III or, IHa or mixtures thereof are generally readily soluble in the above-mentioned solvents and can, after removal of the excess phosgene, directly reacted without further purification with the corresponding β-lactam derivatives of general formula II become.

However, it is also possible to isolate the intermediate of the general formula IHa, if appropriate to desilylate it with a protic solvent, for example water or methanol, to purify it on the basis of its solubility properties and to react in the manner described above.

2319 66 7 -ψ

The ureidocarboxylic acids of the general formula IV can be easily prepared by reacting the pyrimidine derivatives of the general formula III with glycine derivatives of the general formula IX,

CH - GOOH, (II)

in the

., as defined above, obtained. The reaction takes place at temperatures between -20 and +40 C, preferably between 0 and +20 C, in a solvent. As a solvent, e.g. Mixtures of water and organic solvents which are miscible with water may be used, for example acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, ethanol, dimethyl sulfoxide. If appropriate, the use of a halogen-hydrogen-bonding agent is necessary, such as, for example, trialkylamines, such as triethylamine or inorganic bases, such as dilute sodium hydroxide solution.

The 2-substituted 5-amino-4-hydroxypyrimidines of general formula VIII are described in DT-OS 28 08 153.0 and DT-OS ^: 29 10 190.4. :

It has been found that the compounds of formulas I own or I ¹ pharinakologische valuable properties with good tolerability. The active compounds according to the invention can therefore be used for the prophylaxis and chemotherapy of

231966 7 -

and systemic infections in human and veterinary medicine. Examples of diseases which can be prevented or cured by the compounds according to the invention are those of the respiratory tract, the pharynx and the urinary tract; the compounds are particularly effective against pharyngitis, pneumonia, peritonitis, pyelonephritis, otitis, cystitis, endocarditis, bronchitis, arthritis and general systemic infections.

This is made possible by the fact that the compounds of the general formulas I and I ^1, both in vitro and in vivo against harmful microorganisms, both against Gram positive and especially against Gram-negative bacteria and bacteria-like microorganisms act very strong, and they are characterized by a broad spectrum of activity distinguished.

For example, these derivatives may be used to treat and / or prevent local and / or systemic diseases caused by the following agents or by mixtures of the following agents:

Micrococcaceae, such as staphylococci; Lactobacteriaceae, such as streptococci; Neisseriaceae, like Neisseria; Corynebacteriaceae, such as Corynebacteria;

Enterobacteriaceae, such as Escherichiae bacteria of the Coli group,

Klebsiella bacteria, e.g. K. pneumonia;

Proteae bacteria of the Proteus group, e.g. Proteus vulgaris;

Salmonella bacteria, e.g. S. typhimurium; Shigella bacteria, e.g. Shigella dysenteriae; Pseudomonas bacteria, e.g. Pseudomonas aeruginosa; Aeromonas bacteria, e.g. Aeromonas lique facia; Spirillaceae, such as Vibrio bacteria, e.g. Vibrio cholerae;

Parvobateriaceae or Brucellaceae, such as Pasteurella bacteria;

Bruceila bacteria, e.g. Brucella abortus; Haemophilus bacteria, e.g. Haemophilus influenzae;

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: Bordetella bacteria, e.g. Bordetella pertussis; ; Moraxella bacteria, e.g. Moraxella lacunata; ι Bacteroidaceae, such as Bacteroides bacteria; : Fusiform bacteria, e.g. Fusobacterium fusiforme; j Sphaerophorus bacteria, e.g. Sphaerophorus necrophorus; i Bacillaceae, such as aerobic spore formers, e.g. Bacillus

\ anthracis;

anaerobic spore-forming chlostridia, e.g. Clostridium

perfringens;

Spirochaetaceae, such as Borrelia bacteria; r ~ - .. Treponema bacteria, eg Treponema pallidum; Leptospira bacteria, such as Leptospira interrogans.

The above enumeration of pathogens is merely exemplary and by no means limiting.

In the following tables are typical, particularly effective compounds according to the present invention. enumerated. The penicillins can be obtained by the production methods 1 and 2, the cephalosporins by the methods 1 to 3.

231966

Table 1 penicillins of the general formula :

pHCONH

NH

OH

NH

2)

CH ^ OC-O

C 1 H ₁ -OC-0

3) CH., C-

NH

NH

SO ₂ NH ₂

SO ₂ NH ₂

231956 7 - * -

C ^ H ₇ OC- NH

5) (CH 2) ₉ CH-CH ₉ OC-

6) C-H - O-C-

, ^{2 5} A '-NH J / \\ _ SO ₂ NH ₂ -NH

OH

7)

CH ₀ -OC-

³ i -NH-

SOCH-

S)

C_H _c -0-C 2 5 ,,

cyclopropyl

9)

C-H.-O-C-2 5, ι

- NH

10) C H - OC - 2 => II - NH (CH ₂ ) ₃ OH

11) 12)

CH ₃ CO

CH ₀ OC- ³ Il 0

13)

H_NC- NH

231966 7- _a

Z3

Table 2: Cephalosporins of the general formula

OHCOH, NH

po

H ₁ O //

NH

OH COOH

1) CH 1 OC-

2) CH-.OC-

-3 H

3) C ₂ H ₅ OC-

2 5 "0

5) C ₂ H ₅ -O-O

6) CH ₃ CO-

7) CH CO-

8) 0, H ₇ OC-0 sO ₂ NH ₂ -OCO CH.

N ü

NH

_o NH

2 ^

CH3 HH

CH3 N N

NH

-OCO CII.

O ₂ NH

j

CH ₃

NH- ^

^ VSO ₂ NH ₂ _h

CH ₀

231966

9)

10) 11)

12)

13) 14)

C ₂ H ₅ -OC-0

C .H ₃ -OC-0

C-H - O-C-

Δ D ι,

C_H _C -OC-2 5 u

-NH-

OH

SO ₂ NH ₂

-NH-

₁ He 2 5 SO ₂ CH ₃

SO ₂ CH ₃

-NH (CH ₂ J ₃ OH

-NH (CH ₂ V ₃ OH

CH ₃

-CCOCH-

CH,

--OCOCH.

N H

15)

16)

C_H_-O-C-2 5 υ

CH ₃ -CO-

17) CH ₀ -OC-13)

19)

20)

C_H _C -OC-2 5, j

H ₂ NC-0

H_NC

² Il

-NH- / V-OH -NH- / V OH

-NHCH (CH ₃ )

NH

N N

CH,

CH ₃ NN

CH ₃

N_N

1!

CH

-SO ₂ NH ₂

OCOCH

231966 7

The effectiveness of the β-lactam antibiotics according to the invention can be demonstrated by the following examples:

Ί. In vitro experiments:

For the investigations, the method of Reihenverdün-! tion test applied in the microtiter system. The test of ^: substances for bacteriostasis was carried out in liquid medium. The bacteriostatic effect was examined at the following concentrations:

128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.12, 0.06 / μg / ml. A nutrient medium of the following composition was used: 10 g peptone, 8 g meat extract oxoid, 3 g sodium chloride, 2 g sec. Sodium phosphate are mixed with dist. Water to 100 ml (pH 7.2 - 7.4). Only in the test for streptococci 1% glucose was added. The age of the primary cultures was about 20 hours. The segregation of the germ suspension was carried out on the photometer (according to "Eppendorf") (test tube diameter 14 mm, filter 546 nm) on the basis of the turbidity of a barium sulfate comparative suspension, which was produced by a barium sulfate suspension, which by the addition of 3.0 ml 1 % Barium chloride solution in 97 ml of 1% sulfuric acid. After the adjustment, Streptococcus Aronson in the ratio 1:15 and the other test germs in the ratio. 1: 1500 diluted further with saline. ·

16 mg of the respective substance were weighed into 10 ml volumetric flasks and made up to the mark with the solvent. The further dilution series was prepared with distilled water or the respective solvent.

The wells of the microtiter plates were charged with 0.2 ml of nutrient medium, 0.01 ml of the appropriate substance dilution and one drop of germ suspension (0.01 ml) and incubated at 37 ° C. for 18 to 20 hours. A solvent control was always carried.

2 319 6 6 7 -

16

The reading was made macroscopically, whereby the respective limit concentration (= lowest still bacteriostatic effective concentration) was determined.

As test organisms were used:

Staphylococcus aureus SG 511, Escherichia coli ATCC 11 77 5, Pseudomonas aeruginosa Hamburgensis and Pseudomonas aeruginosa Walter, Serratia marcescens ATCC 13 880, Klebsieila pneumoniae ATCC 10 031 and BC 6, Proteus mirabilis Hamburgensis, Proteus rettgeri, Enterobacter cloacae ATCC 13 047, E. coli R + TEM (β-lactamase carrier).

Table 1 below shows the minimum inhibitory concentrations (MIC) determined for typical representatives of the compounds according to the invention:

Ό-cC ~ / 3- ^ -p-Aminosulfonylanilino ^ -hydroxy-5-pyrimidinyl) -uridq7-p-ethoxycarbonyloxybenzylpenicillin sodium = A

D-ci ⁴ - / - 3- {2-p-Aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) ureido ^ -p-methylcarbonyloxybenzylpenicillin sodium = B

Sodium 7- {d- of - / 3- (2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) -ureido / -p-ethoxy-carbonyloxy-phenylacetamide Oji- 3-1 (1-methyl-tetrazol-5-yl ) thiomethyl / ceph-3-em-4-

carboxylate = C

Sodium 7- ^ D- cf - / β- (2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) -ureido7-methylcarbonyloxy-phenylacetamide J- 3 - / (1-methyl-tetrazole-S-yD -thiomethylZ-ceph-S-em-4-carboxylate = D

Minimal inhibitory concentration Staph. E.coli Pseud. L in yug / ml Serr. Kl.pneum. Kl.pneum. Prot. Prot. Ent. E.coli Verbin aureus ATCC Hbg. Pseud.W. marcesc. ATCC BC 6 Mirab. Rettg. cloacae R + TEM fertilize SG 511 11775 ATCC 10031 Hbg. ATCC 13880 13047 0.5 0.25 2 0.25 2 2 0, 12 1 1 > 64 A 0.5 0.25 4 2 0.5 4 2 0.12 2 2 * 64 B 1 0.12 8th 2 0.25 0.5 0.25 0.12 1 0.5 4 C 1 0.5 16 4 2 2 1 0.25 2 4 16 D 2 8-16 8th 8th 4 32 32 2 8th 32 > 64 Azlo 8th cillin 1 8th > 128 8th 2 4 0.5 2 32 4 Cefur > 128 oxime

The compounds mentioned are thus significantly superior to the comparison substances in their effectiveness against typical Gram-negative hospital germs while maintaining the activity against Gram-positive bacteria.

231966 7

The acute toxicity was determined by peroral and subcutaneous application of the compounds of Tables 1 and 2 in the rat in increasing doses.

The LD ₅₀ is the dose at which 50% of the animals die within 8 days. All substances showed an LD ₁₅₀ of more than 4 g / kg when given orally, and LD ₅₀ of more than 3 g / kg when given subcutaneously, ie no animals died at 3 g / kg.

they are therefore nontoxic for the practice.

A number of compounds of the invention have been tested in vivo for experimental infections in mice. E. coli ATCC 11 77 5 was used as the pathogenic bacteria. An intraperitoneal infection with 0.2 ml of a bacterial suspension (with 5% mucin) was set. This corresponds to about 1.4 χ 10 germs E. coli / mouse. Female mice of the strain NMRI were divided into groups of 10 animals each, two groups were left untreated, the remaining groups were treated with different doses of the respective penicillins and cephalosporins according to the invention subcutaneously for the determination of ED.sub.1 (dose in which 50% of the animals survive). It was once an hour _: treated after setting the injection.

The observation period was 7 days in both cases. The! Results of these tests with representative members of the 'penicillins and cephalosporins invention are shown in Table 2.

66 7 '"-g- ~"

, Table 2

In vivo activity in mice : E. coli infection (sc application)

Connection ^ED 5o

A 5.5

B 4,5

c 0.6

D · 3.0

Azlocillin ^ 10O

Cefuroxime ^ 100

2 319 6 5 7

It is another object of the present invention to provide pharmaceutical agents which are valuable in the treatment of infectious diseases in both human and animal.

Preferred pharmaceutical preparations are tablets, dragees, capsules, granules, suppositories, solutions, suspensions, emulsions, ointments, gels, creams, powders and sprays. Advantageously, the active substance is administered in human or veterinary medicine or a mixture of the various active compounds of general formula I in a dosage between 5 and 500, preferably 10-200 mg / kg body weight per 24 hours, optionally in the form of several individual doses. A single dose contains the active substance (s) according to the invention, preferably in amounts of about 1 to about 250, in particular 10 to 60 mg / kg of body weight. However, it may be necessary to deviate from the stated dosages, and. Although depending on the type and body weight of the object to be treated, the nature and severity of Er! illness, the method of preparation and the application of the Medicinal product and the period or interval within which it is administered. Thus, in some cases it may be sufficient to manage with less than the above-mentioned amount of active ingredient, while in other cases, the above-mentioned amount of active ingredient must be exceeded. The specification of the respectively required optimal dosage and mode of administration of the active ingredients can be determined by any person skilled in the art ^; due to his expertise easily done. '

When used as a feed additive, the new compounds may be given in the usual concentrations and preparations together with the feed or with feed preparations or with the drinking water. This can cause infection by gram-negative or gram-positive

2319 66 7 "-

Preventing, ameliorating and / or curing bacteria, as well as promoting growth and improving feed utilization -

The following examples are intended to explain the invention in more detail:

231966 7

3t ;

! Example 1 !

D-of - / 3- (2-p-Aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) ^-: lUreidoJ-p-ethoxycarbonyloxy-benzylpenicillin sodium \

2.8 g (0.01 mol) of S-amino-p-aminosulfonylanilino-hydroxy-pyrimidine are dissolved in 100 ml of dry tetrahydrofuran and heated with 8 g of trimethylsilyldiäthylamin until complete solution to reflux (10 to 30 minutes ). The solution is concentrated to dryness in vacuo, taken up again in 100 ml of tetrahydrofuran and, with ice-cooling, to a solution of 1.06 g of phosgene in 70 ml of dry tetrahydrofuran; dripped. The mixture is stirred for 10 minutes at room temperature and concentrated. then to dryness in vacuo. The remaining solid product is added under ice-cooling with 160 ml of methanol, solution occurs. After a short time, analytically pure 1-hydro-5- (p- '. Aminosulfonylanilino) -oxazolo ^ S, 4-d / pyrimidin-2-one precipitates, which is filtered off with suction and dried.

1.97 g (0.0045 mol) of D-cf-amino-p-ethoxy-carbonyl- is suspended. oxybenzylpenicillin in a solvent mixture of 40 ml of tetrahydrofuran and 10 ml of water. With ice cooling, add up to; Solution triethylamine too. To this solution is added in portions: 1.4 g (0.0045 mol) of 1-hydro-5- (p-aminosulfonylanilino) -oxazolo- \ ^ 5,4-d / pyrimidin-2-one, wherein a decrease in the pH -value is \ below 7 optionally avoided by the addition of triethylamine. The mixture is stirred one hour in an ice bath to leaves, temperature to come to room temperature-'is added to 20 ml of water and the tetrahydrofuran removed in vacuo. The aqueous phase is washed once with acetic ^acid: ester extracted at pH 7.0 and placed under cooling with ice, 1 η \ hydrochloric acid to pH 2.8. The precipitated D (-) - cA / 3- (2-: p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) ureido / -p-ethoxycarbonyloxy-benzylpenicillanic acid is filtered off and dried in vacuo. Stir in dimethylformamide, add the calculated amount of sodium ethylhexanoate and precipitate the sodium salt by dilution with ether.

2 319 6 6 7- x

Yield: 2.12 g (61.5% of theory),

IR spectrum: 1760, 1660, 1600, 1330, 1150 cm ^-1 ; NMR spectrum: (DMSO + CD ₃ OD), signals at ppm:

1,3 (t, 3H), 1,55 (d, 6H), 4,0 (s, 1H), 4,25 (q, 2H) 5,40 (q, 2H), 5,65 (s, 1H), 7.15 (d, 2H), 7.5 (d, 2H), 7.7 (d, 2H), 8.0 (d, 2H), 8.35 (s, 1H).

Example 2

D- ot ~ £ 3 ~ (2-p-Aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) - ureidoZ-p-acetoxybenzylpenicillin sodium

a) 2.36 g (0.005 mol) of D (-) - <J - / "(2-p-Aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) -ureido / - oC- (p-hydroxy-phenyl) acetic acid suspended in 50 ml of glacial acetic acid and to 1.75 g

(0.02 mol) of acetyl chloride.

The reaction mixture is stirred at 20 C for 12 hours. A further 1.7 g of acetyl chloride are added, the mixture is heated briefly to 60 ° C. and then stirred for a further hour at 20 ° C. After adding 100 ml of ether, the product is filtered off with suction, the crystalline product is stirred twice with 100 ml of ether, filtered off with suction and dried . '

This gives 2.4 g (93%) of D (-) - oC- / ~ { 2-p-Aminosulfonylanilino '' 4-hydroxy-5-pyrimidinyl) -uridq / - ^ - (p-acetoxy-phenyl) acetic acid

 Melting point: 214 C (dec.).

b) To a solution of 2.2 g (O, OO425 mol) of D (-) - </ - / _ (2-p-Aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) -urea ^ - «* ⁴ - ( p-acetoxy-phenyl) -acetic acid in a mixture of 50 ml of dimethylformamide and 10 ml of methylene chloride are added 0.46 ml (0.00425 mol) of N-methylmorpholine. It is cooled to -35 C; a solution of 0.41 ml (0.00425 mol) of ethyl chloroformate in 2 ml of methylene chloride is added dropwise.

2319 66 7

After a reaction time of 10 minutes at -35 ° C., 1.34 g (0.00425 mol) of 6-amino-penicillanic acid triethylammonium salt, dissolved in 60 ml of methylene chloride, are added.

The mixture is stirred for 30 minutes at -35 ° C, then removed the cooling and allowed the temperature of the reaction mixture within 30 minutes to 20 C rise.

It is then poured into a mixture of 200 ml of water and 200 ml of methyl acetate, the pH is adjusted with 1N sodium hydroxide solution and the organic phase separated. The aqueous phase is adjusted to pH 2.8 with 1N hydrochloric acid while cooling with ice, the precipitated D (-) - of- / 3 (2-p-Aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) ureido / -p-acetoxybenzylpenicillansäure aspirated , washed with water and dried.

Dissolve in dimethylformamide, add the calculated amount of sodium ethylhexanoate and precipitate the sodium salt by addition of ether.

Yield: 2.1 g (67% of theory), IR spectrum: 1770, 1660, 1600, 1330, 1150 cm ^-1 , NMR spectrum: (DMSO + CD ₃ OD), signals at ppm:

1.55 (d, 6H), 2.20 (s, 3H), 4.0 (s, 1H), 5.40 (q, 2H), 5.60 (s, iH), 7.05 (i.e. , 2H), 7.45 (d, 2H), 7.6 (d, 2H), 7.95 (d, 2H), 8.30 (s, 1H)

Example 3

D-cC- / 3- (4-hydroxy-2- {4'-hydroxycyclohexylamino} -5-pyrimidin yl) -ureido / 'P-ethoxycarbonyloxybenzylpenicillin sodium

'1.12 g of 5-amino-4-hydroxy-2- (4'-hydroxycyclohexylamino) -pyri-; midin (5 mmol) are silylated analogously to Example 1 and reacted with phosgene. The solution of the resulting product in tetrahydrofuran becomes a solution prepared as in Example 1

23198

-M-

the aminopenicillin derivative used there is added dropwise. The

Workup is analogous to Example

Yield: 49%;

IR spectrum: 1770, 1660, 1605, 1330, 1150 cm "'.

, NMR spectrum (DMSO ^ -CD ₃ OD) signals at ppm:

  1.3 (t, 3H), 1.55 (d, 6H), 1.75 (m, 8H), 3.6-4.1

i (m, 1H + s, 1H + m, iH), 4,15 (q, 2H), 5,45 (q, 2H),

! 7.15 (d, 2H), 7.5 (d, 2H), 8.0 (s, iH)

Analogous to Examples 1 and 2, the penicillins of the following table were synthesized:

At-

Yield NMR spectra s, (DMSO + CD ^ OD) signals at ppm

CH-OC- ³ Ά 0

H -

64.5

CH 1 OC- H -NH- <Γ% -SOCH.

3K0

46

6 C₀H_0C- H -NH-(~ \2 5tj \ - /

51

1.55 (d, 6H), 3.90 3H), 4.05 (s, 1H),

5.45 (q, 2H), 5.60

(s, 1H), 7,10 (d, 2H)

7.45 (d, 2H), 7.70

(d, 2H), 7.95 (d, 2H), 8.35 (s, 1H)

1.55 (d, 6H), 2.7 (s, 3H), 3.95 (s, 3H), 4.0 (S, 1H), 5.4 (q, 2H), 5.6 (s, 1H ), 7.15 (d, 2H), 7.5 (d, 2H), 7.75 (d, 2H), 8.0 (d, 2H), 8.35 (s, 1H)

1, 3 (t, 3H), 1, 4-2.0 (m, 10 + 6H), 4.0 (m, 1H + s, 1H), 4.15 (q, 2H), 5.4 (q , 2H), 5.65 (s, 1H), 7.15 (d, 2H), 7.5 (d, 2H), 8.05 (s, 1H)

2319 66 7

example

Yield NMR spectra

(DMSO + CD, OD) signals at ^D

C-H-OC-2 5 (j

H ₉ NC

54.5 1.3 (t, 3H), 1.90 (m, 2H), 3.3 (m, 2H), 3.65 (πι, 2H), 4.0 (s, 1H, 4.1 (q, 2H), 5.45 (q, 2H), 5.6 (s, 1H), 7.15 (d, 2H), 7.5 (d, 2H), 8.05 (s', 1H )

68 1.55 (d, 6H), 4.05

(s, 1H), 5.45 (q-, 2H + s, 1H), 7.7 (d, 2H), 7.95 (d, 2H), 8.36 (s, 1H)

Example 9 '

Sodium 7- J D-C- / ( 2-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) -uridoy-p-ethoxycarbonyloxyphenylacetamido J -3 - / (1- methyltetrazol-5-yl) -thiomethylZ ceph ^ ^ -em carboxylate

a) 2.8 g (0.01 mol) of 5-amino-2-p-aminosulfonylanilino-4-hydroxypyrimidine are slurried in 100 ml of dry tetrahydrofuran and heated with 8 g of trimethylsilyldiäthylamin until complete solution to reflux (10 to 30 minutes) , The solution is concentrated to dryness in vacuo, taken up again in 100 ml of tetrahydrofuran and added dropwise with ice cooling to a solution of 1.06 g of phosgene in 70 ml of dry tetrahydrofuran. The mixture is stirred for 10 minutes at room temperature 'after and then concentrated in vacuo to dryness. The remaining solid product is added under ice-cooling with 160 ml of methanol, solution occurs. After a short time falls

231966 7

analytically pure 1-hydro-5- (p-aminosulfonylanilino) -oxazolo- ' / 5,4-d7pyrimidin-2-one, which is filtered off with suction and dried.

(b) 1.4 g (0.005 mol) of D (-) - <- amino (p-ethoxycarbonyloxyphenyl) acetic acid hydrochloride are suspended in 60 ml of tetra-

    Hydrofuran and added with ice cooling 20 ml of 0.5 N sodium hydroxide solution.

The resulting solution is portion-wise at room temperature with 1.5 g {0.005 mol) of 1-hydro-5- (p-aminosulfonylanilino) -

^: oxazolo / 5,4-d / pyrimidin-2-one, maintaining a pH of 8.0-8.3. After the addition is stirred after one hour at room temperature.

The reaction mixture is mixed with 50 ml of water, the pH is adjusted to 3.0 with 1N hydrochloric acid and extracted twice with 100 ml of ethyl acetate each time.

The combined organic phases are washed with water, dried over sodium sulfate, evaporated in vacuo and the solid residue triturated with ether. This gives 2.4 g (88% of theory) of D (-) - of - £ (2-p-Aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) -ureido / - ^ C - (p-ethoxycarbonyloxyphenyl) - acetic acid

 Melting point: 210 ° C (decomposition).

c) 2.7 g (0.005 mol) of D (-) - <* - / (2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl) -ureido-β- (p-ethoxycarbonyloxyphenyl) Acetic acid are combined with 2.47 g (0.005 mol) of 7-amino-3 - / (i-methyl-tetrazol-5-yl) -thiomethyl / -ceph-3-em-4-carboxylic acid benzhydryl ester in a mixture of 70 ml dissolved dry methylene chloride and 30 ml of dimethylformamide. 1.1 g (O, OO5 mole) of dicyclohexylcarbodiimide are added, with cooling, and the mixture is stirred for 6 hours while cooling with ice. Subsequently, the solvent is removed in vacuo. The backlog will be first. ^:; with 80 ml methanol and then twice with 100 ml ^methylene: lenchlorid well stirred, whereby in each case suctioned off. The remaining solid product is washed with ether and dried.

231966 7

The benzhydryl ester is cleaved with 10 ml of trifluoroacetic acid and 3 ml of anisole in the usual manner and the cephalosporanic acid is converted into the sodium salt with sodium ethylhexanoate in dimethylformamide. \ Yield of sodium salt: 2,57 g (59.5%); IR spectrum: 1760, 1665, 1600 cm ^-1 ;

NMR spectrum (DMSO + CD ₃ OD) signals at ppm:;

1.25 (t, 3H), 3.40 (q, 2H), 3.9 (s, 3H), 4.0 (s, 3H), 4.20 (q, 2H), 4.80 (i.e. , iH), 5.50 (S, 1H), 5.6 (d, 1H>, 7.1 (d, 2H), 7.4-7.7 (dd, 4H), 7.9 (d, 2H), 8.30

The cephalosporins of the following table were synthesized analogously:

example

Yield NMR spectrum

% (DMSOHOD ₃ OD) signals at ppm

10 CH ₀ OC-0

CH ₀ OC- ^J it 0

-NH- ('% -SO ₃ NH

-NH-

-NH-V V

--OCOCH

Il

Il

f CH-

It

CH-

2.05 (s, 3H), 3.45 (q, 2H), 3.90 (s, 3H), 4.80 (q, 2H), 4.90 (d, iH 5.55 (s, 1H), 5.65 (d, iH), 7.0 (d, 2H), 7.35-7.65 (dd, 4H), 7.95 (d, 2H), 8.35 (s, 1H ).

3.5O (q, 2H), 3.95 (s, 3H), 4.0 (s, 3H), 4.3 (q, 2H), 4.95 (d, 1II) 5.50 (s, 1H), 5.60 (d, iH), 7.1 (d, 2H), 7.4-7.7 (dd, 4H), 8.0 (d, 2H), 8.38 (s, 1H )

2.15 (s, 3H), 3.50 (m, 2H), 3.85 (s, 3H), 4.25 (m, 2H), 4.85 (d, iH 5.5 (s, 1H ), 5.65 (d, iH), 7.0 (d, 2H), 7.3-7.85 (m, 6H), 8.35 (s, 1H),

examples

example

-3-9--

Yield 'NMR spectrum

% (DMSO + 0D ₃ OD) signals at ppm

C ₀ H ₁ -OC- ί b "

C ₀ H ₁ -OC-2 5 j,

H ₀ NC-2 ι,

-NH (CH ₉ ) -0H

-NHCH

Il

Il

CH ₁

CH,

N - N

Il "Il

CH-

1.25 (t, 3H), 1.90 (m, 2H), 3.2 (m, 2H), 3.45 (m, 2H), 3.65 (m, 2H), ₍ 3.95 (s, 3H), 4.2 (m, 2H + m, 2H), 4.90 (d, 1H), 5.5 (s, 1H), 5.65 (d, 1H), 7.1 ( (3.2H), 7.4 (d, 2H), ' 8.35 (s, 1H), I

1.15 (d, 6H), 1.3 (t, 3H), 3.50 (q, 2H), 3.8 (broad m, 1H), 3.95 (s, 3H), 4.25 ( m, 4H), 4.90 (d, 1H), 5.50 (a, 1H), 5.65 (d, iH), 7.0-7.4 (m, 4H), 8.05 (s , 1H),

3.45 (q, 2H), 3.95 (s, 3H), 4.25

(m, 2H), 4.95 (d, 1H), 5.50 (s, iH),

5.65 (d, 1H), 7.1-7.4 (m, 4H),

7.65 (d, 2H), 7.95 (d, 2H), 8.36

2319 66 7

The compounds of the general formula I and I ¹ can be incorporated into the customary pharmaceutical application forms, such as tablets, dragees, capsules or ampoules. The single dose in adults is generally between _: 50 and 1000 mg, preferably 100 to 500 mg, the daily dose: between 100 and 4000 mg, preferably 250 to 2000 mg.

Claims (4)

2319 66 7 1. Process for the preparation of new beta-lactams of aiii my teeth 2, method according to item 1a, characterized in that a compound of the general formula II, in which B is hydrogen ", or one of its salts with inorganic or organic bases with a compound of the general formula III a) in water or in water-miscible solvents in the presence of water in a pH range of 6.5 to 8.0 or B) in anhydrous solvents or c) in a mixture of water and water-immiscible solvents in a pH range between 6.5 and δ, 0 is reacted, or that a compound of the general formula II in which B is a SiIy group or another readily cleavable protecting group, with a compound of general formula III in a water- and hydroxyl-free or aprotic solvent, optionally in the presence of a base , is implemented. 2 319 6 6 7 - - ⁸ AP C 07 D / 231 966/1 (59 336 12) E is a water toffatom, is transferred and / or a compound of the general formulas I or I ¹ , in which B is a Wasserstoffatoiü, in their bat he or, by means of inorganic or organic bases, converted into the corresponding salts. 2 319 6 6 7 ¥ 3 CH- CO COIM -H rr in which R, R ₁ and X have the following meanings: R is an aliphatic acyl or alkoxycarbonyl group having 2 to 5 carbon atoms or the aminocarbonyl group X the groups 2C CH- 'CH, and CH ₂ C - CH ₂ D, oos C * COOS 231966 7 wherein D represents a hydrogen atom, an acetoxy, aminocarbonyloxy, pyridinium or 4-aminocarbonylpyridinium group or the group -SHet, where Het is the 1-methyl-tetrazol-5-yl, 1,2,4-TMaCHaZOl-S-Yl -, 3-Methyl-1, 2, 4-thiadiazol-5-yl, 1,3, 4-thiadiazol-2-yl, 2-methyl-T, 3,4-thiadiazol-5-yl or the Represents 4-methyl-5,6-dioxo-1,2,4-triazin-3-yl group and E is a hydrogen atom or an in vitro or in vivo easily cleavable protecting group; R is a hydrogen atom, the 3'-hydroxypropylamino, the cyclopropyl group, the 2'-hydroxyethylamino, 4'-hydroxycyclohexylamino group or a group of the general formula ^ ^R 2 - N, wherein R_ is hydrogen, a branched or is unbranched alkyl or alkenyl group having 1 to 4 carbon atoms or a cycloalkyl radical having 1 to 6 carbon atoms, R is further a group of the general formula -NH (CH ₂ ) η _ wherein η = ο or 1 and R- and R, which may be the same or different, are hydrogen, hydroxy, acetylamino, aminocarbonylamino, nitro, aminocarbonyl, cyano, methylsulfinyl, methylsulfonyl, aminosulfonyl, or the methylaminosulfonyl group, and, if E represents a hydrogen atom, of their physiologically acceptable salts with inorganic or organic bases, characterized in that 31 9 a) for the preparation of a compound of general formula I, or I ¹ in which D has the meanings indicated except the exner pyridinium or Aminöcarbonylpyridiniuingruppe, a compound of the general formula ^ -CH-CQNH, 2 (II) in the R. and X have the meanings given above and D has the abovementioned meanings, with the exception of a pyridinium or aminocarbonylpyridinium group, with a pyrimidine derivative of the general formula , (III) in the ^: R is as defined above and B is the group -NCO, -NHCOCl, -NHCOBr or -NH-COO - // ^ -NO ₃ , or with mixtures of such pyrimidine derivatives of the general formula III, in which B partly the one and partly the other of the abovementioned meanings, is reacted in a solvent and at a pH range between 2.0 and 9.0 at temperatures between -20 ° C and +50 ⁰ C, or ϊ 3 Ό Ό b) for the preparation of a compound of general formula I or I ', in which D has the abovementioned meanings with the exception of a pyridinium or Aminocarbonylpyridiniumgruppe, a Ureidocarbonsaure the general formula rV in the R and R have the meanings given above, or their salts or reactive derivatives, with compounds of the general formula H ₅ N in the X has the abovementioned meanings, with the exception of the formula in which D is pyridinium or aminopyridinium, is reacted between -40 C and + 40 C in the presence of a solvent and optionally in the presence of a base or, 231966 7 c) for the preparation of cephalosporin derivatives of the general ' formulas I or I ¹ , in which D has the meanings of a -S-Het-, ι pyridinium or 4-aminocarbonylpyridiniierungsruppe, e'in compound of the general formula COOH CH ₂ OCOCH ₃ which is mitumfaSt by the general formulas I and I 'and in which R and R have the meanings given above, either with a compound of the general formula Het - S - M (VII) in which Het has the abovementioned meanings and M is a hydrogen atom or an alkali metal or an alkaline earth metal or with pyridine or 4-aminocarbonylpyridine in an organic solvent or in water or in mixtures of these solvents at a pH of the reaction solution between 2 10, advantageously between 4-8, is reacted at a temperature in the range of 0 to 100 C and, if desired, then a compound of the general formulas I or I 'prepared in which E is an easily cleavable protecting group in the free Carboxylic acid of the general formulas I and I ', in the 3. The method according to item 1b, characterized in that as reactive derivatives of the ureidocarboxylic acids of the general formula XV their acid anhydrides, their reactive Bster or reactive amides or their acid halides, as reactive esters of the compounds of general formula V of the diphenylmethyl ester, the t-butyl ester, the TrimethylsiIyI ester or the Ν, Ο-bis-trimethylsilylderivat be used and the reaction in the presence of a base and / or 119 8 6 7 - 16.11.1981 ^ i ^ ww AP C 07 D / 231 966/1 (59 336 12) an organic solvent and / or a condensing agent is carried out and, if desired, the product of general formula I, in which E is a cleavable treasure group, is subsequently converted into a compound of general formula I, in which 1 represents a hydrogen atom. 4. "Process according to item 1 for the preparation of a compound of general formula I or I, raorin in X das_Symbol E is pivaloyloxymethyl, characterized in that a compound of general formula I or I ', in which B represents a hydrogen atom, in its alkali metal salt converted and this with a Pivaloyloxymethylhalogsnid the general formula Hal-CK _o -O-CC- (OH,) _o , C- tlJJ ^ or in Hai is chlorine, bromine or iodine, reacted in a solvent at temperatures between 20 and 4-5 ⁰ C.