NO812543L - ANALOGUE PROCEDURE FOR THE PREPARATION OF PHYSIOLOGICALLY ACTIVE LACTAMES. - Google Patents

Description

This invention relates to the production of new (3-lactams) with the general formula

and optionally their physiologically compatible salts with inorganic or organic bases.

In the general formula I means:

an aliphatic acyl or alkoxycarbonyl group of 2 to 5 carbon atoms or an aminocarbonyl group,

X groups

where

D is a hydrogen atom, an acetoxy-, aminocarbonyloxy-,

pyridinium or 4-aminocarbonyl-pyridinium group or the group -Sliet, where Het means a 1-methyl 1-tetrazol-5-yl-, 1,2,4-thiadiazol-5-yl-, 3-methyl-1,2, 4-thiadiazol-5-yl-, 1,3,4-thiadiazol-2-yl-, 2-methyl-1,3,4-thiadiazol-5-yl- or a 4-methyl-5,6-dioxo- 1,2,4-triazin-3-yl group, and

E. means a hydrogen atom or an in vitro or in vivo easily cleavable protecting group;

R a hydrogen atom, a cyclopropyl group, a 2<1->hydroxyethylamino-, 3'-hydroxypropylamino- or 4'-hydroxycyclohexy1-'amino group or a group of the general formula

where R 2 is hydrogen, a branched

or unbranched alkyl or alkenyl group with 1 to 4 carbon atoms or eh cycloalkyl radical with 3 to 6 carbon atoms,

R further means a group with the general formula

where n = 0 or 1, and R and , which may be the same or different, mean a hydrogen atom, a hydroxy-, acetylamino-, aminocarbonylamino-, nitro-, aminocarbony1-, cyano-, methylsulfinyl-, methylsulfonyl-, aminosulfony1 -.or methylamino-sulfony 1 group.

According to the invention, the carboxyl protecting groups E are those which have also previously been used in connection with penicillins and cephalosporins, especially ester-forming groups, which can be removed by hydrogenolysis or hydrolysis or other treatments under mild conditions, or ester-forming groups which can be easily broken down in the living organism. Examples of. in vitro easily cleavable protecting/protecting groups are e.g. a benzyl, diphenylmethyl, trityl, t-butyl, a 2,2,2-trichloroethyl or a trimethylsilyl group.

If E means a hydrogen atom, according to the invention, pharmaceutically acceptable salts can also be prepared, e.g. alkali or alkaline earth salts, such as sodium, potassium, magnesium or calcium salts, ammonium salts, organic amine salts such as triethylamine or dicyclohexylamine.

If D means pyridinium or aminocarbonylpyridinium, the compounds prepared according to the invention have the general formula Ia

where m means the number 0 or 1.

Preference is given to such compounds of the general formula I wherein

means a methoxycarbonyl-, ethoxycarbonyl-, acetyl- or

aminocarbonyl group,

X is as above indicated, and in X means

E et'hydrogen atom and

D a hydrogen atom, an acetoxy group or the group SHet,

where Het means a 1-methyltetrazol-5-yl-, a 1,3,4-thia-diazol-5-yl- or a 2-methyl-1,3,4-thiadiazol-5-yl group; and

R has the meanings given above.

Particularly preferred compounds of formula I are those in which R represents a group of the general formula

where

R^ means a hydroxy, methylsulfinyl, methylsulfonyl, aminocarbonyl, aminocarbonylamino, aminosulfonyl or methylaminosulfonyl group,

or R represents an m-hydroxy-p-aminosulfonyl anilino-, cyclopropyl-, propylamino-, isopropylamino-, cyclopentylamino-, cyclohexylamino-, 3<1->hydroxypropylamino-, 4'-hydroxycyclohexylamino group,

and R^ and X are as indicated above.

(The 3-lactams of the general formula I can exist in two tautomeric forms (namely of the lactim and of the lactam type). It depends in particular on the solvent used and on the nature of the substituent R, . which of the two forms I and In 1 which dominates:

It will be understood that the initially indicated compounds with the general formula I always include both tautomers.

The compounds of the general formula I can exist in the two possible R and S configurations, and also as a mixture of these configurations, with respect to the chirality center C+' which is denoted by an asterisk. Particular preference is given to such compounds which have the D=R configuration. When the final product is obtained in the D,L form, the pure D and L diastereomers can be prepared by preparative liquid chromatography (HPLC).

The compounds with the general formula I can be prepared as follows: 1. The compounds with the general formula I where D has the stated meaning with the exception of a pyridinium or amino-carbonyl pyridinium group, are prepared by reacting a compound with the general formula

where and X has the meaning given above, and D has the meaning given above with the exception of a pyridinium or aminocarbonylpyridinium group, with a pyrimidine derivative having the general formula

h<y>or R is as above indicated, and B means the group -NCO or et reactive derivative of the group -NHCOOH, for example the groups -NHC0C1, -NHCOBr .or the groups -NCO .and -NHC0C1 being particularly preferred. It is also possible to use mixtures of such pyrimidine derivatives with the general formula III where B partly has one and partly the other of the above meanings, e.g. the groups of each other.

at the same time on the side

If E means a hydrogen atom, the starting compounds with the general formula II can be used in the form of their inorganic or organic salts, e.g. such as triethylammonium salt or sodium salt. The reaction can then be carried out in suitable mixtures of water with such organic solvents as are miscible with water, e.g. ketones such as acetone, cyclic ethers such as

tetrahydrofuran or dioxane, nitriles such as acetonitrile,

formamides such as dimethylformamide, dimethylsulfoxide or alcohols such as isopropanol or in hexametapol. Thereby, the pH of the reaction mixture is kept by adding bases or using buffer solutions in a pH range of approx. 2.0 more

.9.0, preferably between pH 6.5 and 8.0. However, it is also possible to carry out the conversion in anhydrous organic solvents, e.g. halogenated hydrocarbons such as chloroform or

methylene chloride, with the addition of bases, preferably triethyl. amine, diethylamine or N-ethylpiperidine. Furthermore, the reaction can be carried out in a composition of water and a non-water-miscible solvent such as e.g. ether, such as diethyl ether, halogenated hydrocarbons such as chloroform or methylene chloride, carbon disulfide, ketones such as isobutyl methyl ketone, esters such as ethyl acetate, aromatic solvents such as benzene, it being appropriate to stir vigorously and to maintain the pH in a range of approx. pH 2.0 to 9.0, preferably between 6.5 and 8.0, by base addition or by using buffer solutions. One can also carry out the reaction in just water in the presence of an organic or inorganic base or with the addition of buffer substances.

If E means a trimethylsilyl group, i.e. if the silyl derivatives of the compounds of the general formula II are used as starting materials for the method according to the invention (e.g. mono- or suitably the di-trimethylsilyl derivatives silylated on the amino and carboxyl group) and reacting them with the compounds of the general formula III, one usually works expediently in water-<p>g hydroxy1 group-free solvents, for example in halogenated hydrocarbons, e.g. methylene chloride or chloroform, benzene, tetrahydrofuran, acetone or dimethylformamide, etc. The addition of bases is then not necessary, but can in some cases be advantageous to improve the yield and purity of the products. Tertiary aliphatic or aromatic amines such as pyridine or triethylamine, or secondary amines which are difficult to acylate due to steric hindrance, such as dicyclohexylamine, are suitably used as optionally added bases. If E represents one of the other above-mentioned in vitro or in vivo easily cleavable protecting groups, e.g. a dif enyl methyl ester group or, a pivaloyloxymethyl group, it is also recommended to work in an aprotic solvent, e.g. in absolute methylene chloride, chloroform, tetrahydrofuran or dimethylformamide.

The amount of bases used is determined, for example, by a specific pH value to be maintained. When a pH measurement or adjustment is not carried out or is not possible, or practical due to insufficient amounts of water in the diluent, preferably 1.0 to 2.0 molar equivalents are used for the non-silylated compounds of the general formula II base. When using silylated compounds, preferably up to 1 molar equivalent of base is used.

As bases, all the organic and inorganic bases that are usually used in organic chemistry can be used, such as alkali and alkaline earth hydroxides, alkaline earth oxides, alkali and alkaline earth carbonates and hydrogen carbonates, ammonia, primary, secondary and tertiary aliphatic_ and aromatic amines such as heterocyclic bases. Examples include sodium, potassium and calcium hydroxide, calcium oxide, sodium and potassium carbonate, sodium and potassium hydrogen carbonate, diethylamine, methylethylamine, triethylamine, hydroxyethylamine, aniline, dimethylaniline, pyridine and piperidine. When using the silylated starting materials, however, one must take into account the above-mentioned limitations with regard to the nature of the bases.

All common buffer mixtures can be used as buffer systems, e.g. phosphate buffers, citrate buffers and tris-(hydroxymethyl)-amino-methane buffers.

The reaction temperatures can be varied within a large range. Usually you work between -20 and +50°C, preferably between 0 and +20°C.

The reaction components with the general formulas II and III can be reacted in equimolar amounts from the beginning. However, in some cases it may be appropriate to use one of the two reaction components in excess in order to facilitate the purification of the final product or to increase the yield.

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

where

R and R^ have the meanings given above, their salts or reactive derivatives, with compounds of the general formula V

where

X has the meanings given above, with the exception of the formula where D means pyridinium or aminocarbonylpyridinium.

As reactive derivatives of the ureidocarboxylic acids with the general formula IV, their acid anhydrides can be used, for example, such as those that can be derived from chloroformate esters, e.g. chloroformate ethyl or isobutyl ester, or their reactive esters such as p-nitrophenyl esters or N-hydroxysuccinimide esters, or their reactive amides such as N-carbonylimidazole, and also their acid halides such as the corresponding acid chloride, or their acid azides.

In principle, however, all coupling methods can be used, as is known from (3-lactam chemistry

The 7-aminocephalosporanic acid or penicillanic acid derivatives with the general formula V are advantageously used in the form of an in vitro or in vivo easily cleavable derivative. For this purpose, these are compounds of the general formula V where E has the meanings given at the beginning with the exception of a hydrogen atom, and particularly preferred derivatives are the diphenylmethyl ester, the t-butyl ester, the trimethylsilyl ester or the N,0-bis-trimethylsilyl derivative .

For example, the ureidocarboxylic acids, their salts or their reactive derivatives are reacted with the 7-aminocephalosporan or 6-aminopenicillanic acid derivatives in a solvent at temperatures between -40 and +40°C, possibly in the presence of a base. If it e.g. an anhydride of ureidocarboxylic acid is used,

such as the anhydride with ethyl chloroformate, re-

the mixture under cooling for example at -40 to +10°C in a solvent such as acetone, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane, hexmetapol or in a mixture of these solvents. If, for example, one reacts an N-hydroxy-succinimide ester of the ureidocarboxylic acid with deriv-

vater of the general formula V, the reaction is preferably carried out at 0 to 20°C in the presence of a base such as triethylamine, in a solvent such as dimethylformamide, dichloromethane, dioxane or in a mixture of such solvents.

The reaction of a ureidocarboxylic acid of the 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. e.g. in the presence of N , N 1 -dicyclohexylcarbodiimide.

3. Cephalosporin derivatives of the general formula I where p means a -S-Het-', pyridinium or 4-aminocarbonylpyridinium group can be prepared by reacting a compound with the

. general formula VI

where

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

where Het has the meanings given above, and M means a hydrogen atom or an alkali metal or an alkaline earth metal, or with pyridine resp. 4-aminocarbonylpyridirt. A compound of formula VI is reacted here, for example, with 5-methyl-2-mercaptol-1,3,4-thiadiazole in a solvent such as water, methanol, ethanol, acetone, methyl ethyl ketone, tetrahydrofuran, acetonitrile, acetic acid ethyl ester, dimethoxyethane, dimethylformamide, dimethyl sulfoxide,

chloroform or a mixture of these solvents. Preferably, a strong polar solvent such as

water, acetonitrile or the like. When using water that

solvent, the pH value in the reaction mixture is advantageously kept at 2 to 10 and in particular at 4 to 8. The desired pH value

can be adjusted by adding a buffer solution such as sodium phosphate. The reaction conditions are not subject to any special restrictions. Normally, the reaction is carried out at a temperature in the range from 0 to 100°C over a period of a few hours.

The new compounds produced according to methods 1-3, where E means an in vitro easily cleavable protective group, can be transferred by known methods from cephalosporin or penicillin chemistry to the free carboxylic acids (E = hydrogen) with the general formula I. Thus, for example, the trimethylsilyl group can be easily removed by aqueous hydrolysis, or the diphenylmethyl ester group can, for example, be removed by hydrolytic cleavage with trifluoroacetic acid. This elimination of the protecting group is generally known.

Likewise, antibiotics with formula I or I" where E means a hydrogen atom, is transferred to acyloxyalkyl esters where E e.g. means a pivaloyloxymethyl residue,

by reacting an alkali salt of the free carboxylic acid, e.g. a sodium or potassium salt, with a pivaloyloxymethyl halide of the formula

where Hal means chlorine, bromine or iodine. Other suitable acyloxyalkyl halides are e.g. ' chloromethyl acetate, bromo tyl propionate or 1-bromomethyl acetate.

The preparation of the acyloxyalkyl esters of formula I is carried out by reacting the appropriate alkali salt of the parent acid in an inert solvent with a small molar excess of the iodo, bromo or chloroalkyl ester, such as pivaloyloxymethyiodide, at room temperature or slightly elevated temperature up to approx. 40 to 45°C. As solvents, for example, acetone, tetrahydrofuran, dioxane, dimethylformamide or methylene chloride can be used.

The processing of the reaction mixtures obtained by the aforementioned methods after completion of the reaction is carried out according to ■ methods that are common for 3-1actam antibiotics, and the same applies to the isolation and purification of the end products, for example for releasing the acid or transferring it to second

salts using inorganic or organic bases. For the preparation of the potassium or sodium salts, it is particularly convenient to precipitate these salts from an alcoholic-etheric solution of the free acid by adding potassium or sodium 2-ethylhexanoate, or to react the free acid with a suitable amount sodium bicarbonate under pH control and cooling and subsequent freeze-drying.

The starting materials with formula II are known or can be prepared analogously to known substances by methods known per se, e.g. by acylation of the known amino-lactams of formula IV and, if desired, subsequent reaction of the thus obtained cephalosporanic acid derivatives of formula II (D=- -OCOCH^) with thiols of formula Het-SH.

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

where R is as above, with phosgene. This reaction is preferably carried out in a non-hydroxyl group-containing solvent such as tetrahydrofuran, methylene chloride, chloroform, dimethoxyethane or hexametapol at temperatures between -40 and +60°C, preferably between -10 and +20°C. It is then recommended to bind the hydrogen chloride formed using equimolar amounts of an inert, organic base such as triethylamine or pyridine. An excess of pyridine can also be used as a solvent. If the relevant aminopyrimidines of the general formula VIII should be poorly soluble in one of the mentioned solvents, the phosgene reaction can also be carried out in a heterogeneous phase. Furthermore, the aminopyrimidines of the general formula VIII can by treatment with a silylating agent such as hexamethyldisilazane or trimethylchlorosilane/triethylamine, trimethylsilyldiethylamine or N,0-bis-trimethylsilylacetamide, is transferred to a usually in the mentioned solvents very easily soluble, single or, according to

to the replaceable hydrogen atoms present, polysilylated aminopyrimidine, which then reacts with phosgene to the corresponding compounds of the general formula III. Depending on the nature of the solvent, the temperature, the amount and the nature of the base used, either predominantly the corresponding isocyanate or carbamic acid halide or a mixture of these two compounds is formed. Depending on the reaction conditions, the compound with the general formula III can also exist partially or completely as a dihydrooxazolo-pyrimidine with the general formula Illa that is isomeric with the isocyanates

or one by prior silylation, depending on the nature of the substituent R as a single or multi-silylated analogue.

The starting compounds with the general formula III or Illa or their mixtures are usually well soluble in the above-mentioned solvents and, after removal of excess phosgene, can be reacted directly without further purification with the appropriate 3-lactam derivatives of the general formula II.

However, it is also possible to isolate the intermediate with the general formula Illa, optionally desilylate it with a protic solvent, e.g. water or methanol, purify it on the basis of its solubility characteristics and react it on. the way described above.

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

where

R^ is as stated above. The reaction takes place at temperatures between -20 and +40°C, preferably between 0 and +20°C, in a solvent. Solvents can be used, for example, mixtures of water and organic solvents that are miscible with water, e.g. acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, ethanol or dimethylsulfoxide. Optionally, it is necessary to use a hydrogen halide binding agent, and suitable such agents are, for example, trialkylamines such as triethylamine, or inorganic bases such as dilute caustic soda.

The 2-substituted 5-amino-4-hydroxypyrimidines of the general formula VIII are described in the German Official Gazettes 28 08 153.0 and 29 10 190.4.

It has been found that the compounds with the general formulas I resp. -I' possesses valuable pharmacological properties and has good compatibility. The new active substances can thus be used for the prevention and chemotherapy of local and systemic infections in human and animal medicine. ■ As diseases that can be prevented or can be healed, for example those in the respiratory tract, oral cavity and urinary tract can be mentioned. 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 with the general formulas I or I' both in vitro and in vivo works very strongly against harmful microorganisms, both against gram-positive and also especially against gram-negative bacteria and bacteria-like microorganisms, and they are distinguished by a broad spectrum of action.

With these derivatives, one can, for example, treat and/or prevent local and/or systemic diseases caused by the following microorganisms or by mixtures of the following microorganisms:

Micrococcaceae, such as staphylococci,

Lactobacteriaceae, such as streptococci,

Neisseriaceae., such as 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.. thyphimurium,

Shigella bacteria, e.g. Shigella dysenteriae,

Pseudomonas bacteria, e.g. Pseudomonas aeruginosa, Aeromonas bacteria, e.g. Aeromonas lique faciens, Spirillaceae, such as Vibrio bacteria, e.g. Vibrio cholerae, Parvobacteriaceae or Brucéllaceae, such as Pasteurella bacteria,

Brucella bacteria, e.g. Brucella abortus,

Haemophilus bacteria, e.g. Haemophilus influenzae,

Bordetella bacteria, e.g. Bordetella pertussis, Moraxella bacteria, e.g. Moraxella lacunata,

Bacteroidaceae, such as Bacteroides bacteria,

Fusiform bacteria, e.g. Fusobacterium fusiforme, Sphaerdphorus bacteria, e.g. Sphaerophorus necrophorus,. Bacillaceae, such as aerobic spore formers, e.g. Bacillus anthracis, anaerobic spore-forming clostridia, e.g.. Chlostridium perfringens, Spirochaetaceae, such as Borrelia bacteria,

Treponema bacteria, e.g. Treponema pallidum,

Leptospira bacteria, such as Leptospira interrogans.

The above list of microorganisms are examples only

and shall not represent any limitation.

In the following tables, typical, particularly active compounds produced according to the invention are indicated. The penicillins can be produced by production methods 1 and 2 and the cephalosporins by production methods 1 to 3.

The effect of the 3-lactam antibiotics produced according to the invention can be demonstrated, for example, by the following investigations:

1. In vitro experiments

For the investigations, the method was serial dilution samples

in microtiter system used. The examination of the compounds with regard to bacteriostasis was carried out in liquid medium. The bacteriostasis effect was examined at the following concentrations:

128; 64; 32; 16; 8; 4; 2; 1; 0.5; 0.25; 0.12; 0.06 ug/ml. A nutrient medium was used with the following composition: 10 g peptone, 8 g meat extract oxoid, 3 g sodium chloride and 2 g sec. sodium phosphate is diluted with distilled water to 100 ml (pH 7.2-7.4). Only when testing against streptococci was 1% glucose added. The age of the primary cultures was approx. 20 hours. The setting of the bacterial suspension was made on a photometer (according to "Eppendorf") (tube cross-section 14 mm, ■ filter 546 nm) on the basis of the turbidity of a barium sulfate comparison suspension, which was obtained with a barium sulfate slurry formed by addition of 3.0 ml of 1% barium chloride solution to 97 ml of 1% sulfuric acid. After the setting, Streptococcus Aronson in a ratio of 1:15 and the other test bacteria in a ratio of 1:1500 were further diluted with a sodium chloride solution. 16 mg of the test compound were weighed into 10 ml volumetric flasks and diluted with the solvent to the mark. The further dilution series was made with distilled water or the appropriate solvent.

The wells in the microtiter plates were filled with 0.2 ml of nutrient medium, 0.01 ml of the desired dilution of the test compound and with a drop of bacterial suspension (0.01 ml) and cultured for 18 to 20 hours at 37°C. A solvent control was always included.

The reading was carried out macroscopically, so that the relevant limit concentration (= lowest, still bacteriostatically active concentration) was obtained.

The following organisms were used as test organisms:

Staphylococcus aureus SG 511, Escherichia coli ATCC 11 775, Pseudomonas aeruginosa Hamburgensis and Pseudomonas aeruginosa

Walter, Serratia marcescens ATCC 13 880, Klebsiella pneumoniae ATCC 10 031 and BC 6, Proteus mirabilis Hamburgensis, Proteus rettgeri, Enterobacter cloacae ATCC 13 047, E. coli R+TEM (3-lactamase carrier).

In the following table 1, the minimal inhibitory concentrations (MIC) found for typical representatives of the new compounds are indicated:

The acute toxicity was determined by oral and subcutaneous administration of the compounds according to Tables 1 and 2 to white laboratory mice in increasing doses.

LD5Q is the dose that causes 50% of the animals to die within 8 days of administration. All compounds show an LD5Q of over 4 g/kg when administered orally, and an LD5q Pa of over 2 g/kg when administered subcutaneously, i.e. at 2 g/kg no animals died, and the compounds are thus practically non-toxic.

A number of the new compounds were investigated in vivo on experimental infections in mice. E. coli ATCC 11 775 was used as pathogenic bacteria. An intra-peritoneal infection was induced with 0.2 ml of a bacterial suspension (with 5% mucin). This corresponds to approx. 1.4 x 10 microorganisms of the species E. coli/mouse. Female mice of the strain NMRI were divided into groups of 10 animals each, two groups were left untreated, and the other groups were treated subcutaneously with different doses of the relevant new penicillins and cephalosporins to determine the ED^Q (dose at which 50% of the animals survived) . Treatment was carried out once 1 hour after the infection.

The observation period was 7 days in both cases. The results of these tests with representative compounds prepared according to the invention are shown in table 2.

The new compounds can be introduced into pharmaceutical preparations for the treatment of infectious diseases in both humans and animals.

As preferred pharmaceutical preparations can be mentioned

tablets, dragées, capsules, granules, suppositories, solutions, suspensions, emulsions, ointments, gels, creams, powders and spray preparations. Advantageously, the active substance or a mixture of different active substances with the general formula I is used in human or veterinary medicine in a dosage between 5 and 500, preferably 10-200 mg/kg body weight per day, - possibly in the form of several individual administrations. A single administration contains the active substance or active substances, preferably in amounts of approx. 1 to approx. 250, in particular 10 to 60 mg/kg body weight. However, it may be necessary

to deviate from the aforementioned dosages, and in particular depending on the nature and body weight of the individual to be treated, the nature and

■the degree of the disease, the nature of the preparation and the form of administration of the medicine and also the period of time resp. interval during which the administration takes place. Thus, in some cases it may be sufficient to use less than the amount of active substance indicated above, while in other cases it is necessary to use more than the indicated amount of active substance. Determining the optimum dosage and form of administration required at any given time for the active substances can easily be carried out by any expert on the basis of his professional knowledge.

When it concerns use as pre-additives, the new compounds can be used in normal concentrations and preparations together with the precursor or with precursor preparations or with the drinking water. Thereby, an infection with gram-negative or gram-positive bacteria can be prevented, improved and/or cured, and likewise an improvement in growth and an improvement in utilization can be achieved.

The following examples further illustrate the invention: Example 1

D-α-[3-(2-β-aminosulfonyl anilino-4-hydroxy-4-pyrimidinyl)-. ure ido] - p- ethoxycarbonyl loxy- benzyl lpene. icillin sodium

2.8 g (0.01 mol) of 5-amino-2-p-aminosulfonylanilino-4-hydroxy-pyrimidine are slurried in 100 ml of dry tetrahydrofuran and heated under reflux with 8 g of trimethylsilyldiethylamine until complete dissolution is obtained (10 to 30 minutes) . The solution is evaporated to dryness in vacuo, taken up again in 100 ml

tetrahydrofuran and added dropwise under ice-cooling to a solution of 1.06 g of phosgene in 70 ml of dry tetrahydrofuran. Man about-

stir for 10 minutes at room temperature and then evaporate to dryness in vacuo. The remaining solid product is added to 160 ml of methanol under ice cooling, whereby dissolution takes place. After a short time, analytically pure 1-hydro-5-(p-aminosulfonyl anilino)-oxazolo[5,4-d]pyrimidin-2-one precipitates, which is filtered off with suction and dried.

1.97 g (0.0045 mol) of D-α-amino-p-ethoxy-carbonyloxy-behzylpenicillin are suspended in a solvent mixture of 40 ml of tetrahydrofuran and 10 ml of water. Under ice-cooling, triethylamine is added until everything is dissolved. To this solution, 1.4 g (0.0045 mol) of 1-hydro-5-(p-aminosulfonyl anilino)-oxazolo-[5,4-d]pyrimidin-2-one is added in portions, thereby preventing the pH value from falling under 7 during the addition of triethylamine. The mixture is stirred for 1 hour in an ice bath, the mixture is allowed to come to room temperature, 20 ml of water is added and the tetrahydrofuran is removed in vacuo. The aqueous phase is decanted once with ethyl acetate at pH 7.0 and adjusted to pH 2.8 with 1N hydrochloric acid under ice cooling. The precipitated D(-)-a-[3-(2-p-aminosulfonyl anilino-4-hydroxy-5-pyrimidinyl)-ureido]-p-ethoxycarbonyloxy-benzylpenicillanic acid is suctioned off and dried in vacuo. Stir in dimethylformamide, add the calculated amount of sodium ethyl hexanoate and precipitate the sodium salt by dilution with ether.

Yield: 2.12 g (61.5% of the theoretical),

IR spectrum: 1760, 1660, 1600, 1330, 1150 cm"1;

NMR spectrum: (DMSO + CD30D), signals at ppm:

1.3 (t,3H), 1.55 (d,6H), 4.0 (s,lH), 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-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido]-p-acetoxy- benzylpenicillin- sodium

a) 2.36 g (0.005 mol) D(-)-α-[(2-p-aminosulfonyl anilino-4-hydroxy-5-pyrimidinyl)-ureido]-α-(p-hydroxy-phenyl)acetic acid

is suspended in 50 ml of glacial acetic acid, and 1.75 g (0.02 mol) of acetyl chloride is added to this suspension.

The reaction mixture is stirred for 12 hours at 20°C. A further 1.75 g of acetyl chloride is added, heated briefly to 60°C and then stirred for a further 1 hour at 20°C. After the addition of 100 ml of ether, suction is carried out, the crystalline product is stirred twice with 100 ml of ether each time, suction is taken off and dried. 2.4 g (93%) of D(-)-α-[(2-p-aminosulfonyl anilino-4-hydroxy-5-pyrimidinyl)-ureido]-α-(p-acetoxy-phenyl)acetic acid are obtained.

Melting point: 214°C (decomposition).

b) To a solution of 2.2 g (0.00425) D(-)-α-[(2-p-aminosulfonylanilinino-4-hydroxy-5-pyrimidinyl)-ureido]-α-(p-acetoxy- phenyl)acetic acid in a mixture of 50 ml of dimethylformamide and 10 ml of methylene chloride is added 0.46 ml (0.00425 mol) of N-methyl-morpholine. It is cooled to -35°C and a solution of 0.41 ml (0.00425 mol) chloroformic acid ethyl ester in 2 ml methylene chloride is added dropwise.

After a reaction time of 10 minutes at -35°C is added

1.34 g (0.00425 mol) 6-aminopenicillanic acid triethylammonium salt, dissolved in 60 ml of methylene chloride.

The mixture is stirred for 30 minutes at -35°C, then the cooling is removed and the temperature of the reaction mixture is allowed to rise to 20°C over the course of 30 minutes. It is then poured into a mixture of 200 ml of water and 200 ml of methyl acetate, the pH value is adjusted to 7 with IN caustic soda, and the organic phase is separated. Under ice-cooling, the aqueous phase is adjusted to pH 2.8 with 1N hydrochloric acid, the precipitated D(-)-a-[3-(2-p-aminosulfonyl anilino-4-hydroxy-5-pyrimidinyl)ureido]-p- acetoxy-benzylpenicillanic acid is filtered off, washed with water and dried.

It is dissolved in dimethylformamide, the calculated amount of sodium ethyl hexanoate is added and the sodium salt is precipitated by adding ether. •

Yield: 2.1 g (67% of the theoretical),

IR spectrum: 1770, 1660, 1600, 1330, 1150 cm"<1>,

NMR spectrum: (DMSO + CD30D), signals at ppm:

1.55 (d, 6H), 2.20 (s, 3H), 4.0 (s, 1H), 5.40.

(q.,2H), 5.60 (s,1H), 7.05 (d,2H), 7.45 (d,2H),

7.6 (d,2H), 7.95 (d,2H), 8.30 (s,1H).

Example 3

D-a-[3-(4-hydroxy-2-{4'-hydroxycyclohexylamino}-5-pyrimidin-yl)- ureido]- p -ethoxycarbonyloxy- benzylpenicillin sodium

1.12 g of 5-amino-4-hydroxy-2-(4'-hydroxycyclohexylamino)-pyrimidine (5 mmol) is silylated analogously to example 1 and reacted with phosgene. The solution of the obtained product in tetrahydrofuran is added dropwise to a solution prepared in example 1

ning of the aminopenicillin derivative used there. Processing is carried out analogously to example 1.

Yield: 49%; ...

IR spectrum: 1770, 1660, 1605, 1330, 1150 cm"<1>.

NMR spectrum (DMS0+CD30D) signals at ppm:

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

(m,lH + s,lH + m,lH), 4.15 (q,2H), .5.45 (q,2H), . 7.15 (d,2H), 7.5 (d,2H), 8.0 (s,1H).

Analogous to examples 1 and 2, the penicillins in the following table were synthesized:

Example 9

Sodium 7-{D-a-[(2-aminosulfonylanilino-4-hydroxy-5-pyrimidin-yl)-ureido]-p-ethoxycarbonyloxy-phenylacetamido}-3-[(1-methyl-tetrazol-5-yl)-thiomethyl ]- cef- 3- em- 4- carboxylate

a) 2.8 g (0.01 mol) of 5-amino-2-p-aminosulfonyl anilino-4-hydroxy-^pyrimidine are suspended in 100 ml of dry tetrahydrofuran and

heated under reflux with 8 g of trimethylsilyldiethylamine until complete dissolution is obtained (10 to 30 minutes). The solution is evaporated to dryness in vacuo, taken up again in

100 ml of tetrahydrofuran and added dropwise under 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 and then evaporated to dryness in vacuo. The remaining solid product is added to 160 ml of methanol under ice-cooling, whereby dissolution takes place. After a short time, analytically pure 1-hydro-5-(p-aminosulfonyl anilino)-oxazolo-[5,4-d]pyrimidin-2-one precipitates, which is filtered off with suction and dried.

b) 1.4 g (0.005 mol) of D(-)-α-amino-(p-ethoxy-carbonyloxy-phenyl)acetic acid hydrochloride are suspended in 60 ml of tetrahydrofuran

and adds 20 ml of 0.5 N caustic soda under ice-cooling.

The resulting solution is added portionwise at room temperature to 1.5 g (0.005 mol) of 1-hydro-5-(p-aminosulfonylanilino)-oxazolo[5,4-d]pyrimidin-2-ori, a pH value of 8.0 - 8.3 is maintained. After the addition is finished, stir further for 1 hour<y>ed at room temperature. 50 ml of water is added to the reaction mixture, the pH value is adjusted to 3.0 with IN hydrochloric acid, and extraction is carried out 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 is triturated with ether. 2.4 g (88% of the theoretical) of D(-)-a-[(2-p-amino-sulfonyllanylino-4-hydroxy-5-pyrimidinyl)-ureido]-a-(p -ethoxy-carbonyloxy-phenyl)acetic acid.

Melting point: 210°C (decomposition).

c) 2.7 g (0.005 mol) of D(-)-α-[(2-p-aminosulfonyl anilino-4-hydroxy-5-pyrimidinyl)-ureido]-α-(p-ethoxycarbonyloxy-phenyl)-acetic acid are dissolved, together with 2.47 g (0.005 mol) of 7-amino-3-[(1-methyl-tetrazol-5-yl)-thiomethyl]-cef-3-em-4-carboxylic acid benzhydryl ester in a mixture of 70 ml of dry methylene chloride and 30 ml of dimethylformamide. During cooling, 1.1 g (0.005 mol) of dicyclohexylcarbodiimide is added and stirred for 6 hours under ice cooling. The solvent is then removed in vacuo. The residue is first thoroughly stirred with 80 ml of methanol and then twice with 100 ml of methylene chloride each time, suction being carried out in each case. The remaining solid product is washed with ether and dried. The benzhydryl ester is cleaved in the usual way with 10 ml of trifluoroacetic acid and 3 ml of anisole, and the cephalosporanic acid is transferred to the sodium salt with sodium ethyl hexanoate in dimethylformamide. Yield of sodium salt: '2.57 g (59.5%); IR spectrum: 1760, 1665, 1600 cm"<1>;

NMR spectrum (DMSO + CD30D) 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 (d,lH), 5.50 (s,lH), 5.6 (d,lH), 7.1 (d,2H), 7.4- 7.7 (dd,4H), 7.9 (d,2H), 8.30 (s,1H).

Analogously, the cephalosporins in the following table were synthesized:

The compounds with the general formula I and 1<1> can be incorporated into the usual, pharmaceutical application forms such as

tablets, dragées, capsules or ampoules. The single dose for adults is usually between 50 and 1000 mg, preferably 100 to 500 mg, and the daily dose is between 100 and 4000 mg, preferably 250 to 2000 mg.

Claims (5)

1.'Analogy method for the production of new physiological active 3-lactams with the general formulas where R, R^ and X have the following meanings: R^ is an aliphatic acyl or alkoxycarbonyl group with 2 to 5 carbon atoms or an aminocarbonyl group, . where D is a hydrogen atom, an acetoxy-, aminocarbonyloxy-, . pyridinium or 4-aminocarbonyl-pyridinium group or the group -SHet, where Het means a 1-methyl-tetrazol-5-yl-, 1,2,4-thiadiazol-5-yl-, 3-methyl-1,2,4- thiadiazol-5-yl-, 1,3,4-thiadiazol-2-yl-, 2-methyl-1,3,4-thiadiazol-5-yl- or 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 light of cleavable protecting group; R is a hydrogen atom, a 3'-hydroxypropylamino-, cyclopropyl-, 2<1->hydroxyethylamino-, 4'-hydroxycyclohexylamino group or a group of the general formula where R_ means hydrogen, a branched or unbranched alkyl or alkenyl group with 1 to 4 carbon atoms or a cycloalkyl radical with 1 to 6 carbon atoms, R further means a group with the general formula where n = 0 or 1, and R^ and R^, which may be the same or different, mean a hydrogen atom, a hydroxy-, acetylamino-, aminocarbonylamino-, nitro-, aminocarbonyl-, cyano-, methylsulfinyl-, methylsulfonyl -, aminosulfonyl or methylaminosulfonyl group, and, when E means a hydrogen atom, their physiologically compatible salts with inorganic or organic bases, .characterized by.a-t a) for the preparation of a compound of the general formula I resp. 1<1>where D has the indicated meanings with the exception of -. else a pyridinium or aminocarbonylpyridinium group, a compound of the general formula is reacted where R^ and -X have the meanings given above, and D has the meanings given above with the exception of a pyridinium or aminocarbonylpyridinium group, with a pyrimidine derivative with the general formula where R is as above, and B means the groups -NCO, -NHC0C1, -NHCOBr or or with mixtures thereof pyrimidine derivatives with the general formula III, where B partly has one and partly the other of the above meanings, in a solvent and at a pH range between 2.0 and 9.0 at temperatures between -20 and +50°C, or b) for the preparation of a compound of the general formula I resp. I<1>, where D has the meanings given above with the exception of a pyridinium or aminocarbonylpyridinium group. a ureidocarboxylic acid with the general formula is reacted where R and R^ have the meanings given above, or its salts or reactive derivatives, with compounds having the gene real formula where X has the meanings given above with the exception of the formula where D means pyridinium or aminocarbonylpyr.idinium, between -40 and +40°C in the presence of a solvent and. optionally in the presence of a base, or c) for the preparation of cephalosporin derivatives with the general formulas I or In' where D means a -S-Het-, pyridinium or 4-aminocarbonylpyridinium group, a compound is reacted with the general formula which are covered by the general formulas I resp. I' and where R and R^ have the meanings indicated above, either with a compound of the general formula' where Het has the meanings indicated above, and M means a hydrogen atom or an alkali metal or an alkaline earth metal, or with pyridine resp. 4-aminocarbonylpyridine in an organic solvent or in water or in mixtures of these solvents at a pH value in the reaction solution between 2 and 10, advantageously between 4 and 8, at a temperature in the range from 0 to 100°C , and optionally, a thus prepared compound with the general formulas I or I' where'E denotes an in vitro easily cleavable protective group is then converted into it. free carboxylic acid with the general formulas I resp. I' where E is a hydrogen atom, and/or a compound of the: general formulas I or I<1>where E is a hydrogen atom, are converted to their esters or, with the help of inorganic or organic bases, to the desired salts. 2. Process as stated in claim la,b for the production of D-a-[3-(2-^-p-aminosulfony lanilino-4-hydroxy-5-pyrimidinyl)-ureido]-p-ethoxycarbonyloxy-benzylpeniellin sodium, characterized by using starting materials where R means aminosulfonyl anilino, R^ means ethoxycarbonyl, and X has the formula A stated in claim 1, and the compound produced is converted to the sodium salt. 3. Process as stated in claim la,b for the production of D-a-[3-(2-p-aminosulfonyl anilino-4-hydroxy-5-pyrimidinyl)- ureido]-p-methylcarbonyloxy-benzylpenicillin-sodium, characterized in that starting materials are used where R means aminosulfonyl anilino, R-^ means methyl-carbonyl, and X has the formula A specified in claim 1, and the compound produced is converted to the sodium salt. 4. Process as stated in claim 1 for the production of sodium 7-{D-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido]-p-methylcarbonyloxy-phenylacetamido}-3-[ (1-methyl-tetrazol-5-yl)-thiomethyl]-cef-3-em-4-carboxylate, characterized in that starting materials are used where R means aminosulfonyl anilino, R^ means methyl-carbonyl, and X has the stated in claim 1 formula B where D means (1-methyl-tetrazol-5-yl)-thio, and the compound produced is converted to the sodium salt. 5. Process as stated in claim 1 for the preparation of sodium 7-{D-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido]-p-ethoxycarbonyloxy-phenylacetamido}-3- [(1-methyl-tetrazol-5-yl)-thiomethyl]-cef-3-em-4-carboxylate, characterized in that starting materials are used where R means aminosulfonyl anilino, R^ means ethoxycarbonyl, and X has the formula specified in claim 1 B where D means (1-methyl-tetrazol-5-yl)-thio, and the compound produced is converted to the sodium salt.