NO813806L - ANALOGUE PROCEDURE FOR THE PREPARATION OF NEW PENCILLINES - Google Patents

Description

This invention relates to the preparation of new penicillins of the general formula I

and their physiologically compatible salts with inorganic or organic bases, which are suitable for use in pharmaceuticals.

In the above general formula I means:

a) A a phenyl group and

The R group with the general formula II

where n is 0 or 1, and R1, if n is 0, means the groups -SO2-R4, -SO-R4, -SO2-NH2, -SO2"NH-R4 or -SO2"N(R4)2, and, if n is 1, R^ means the above-mentioned groups and also a hydrogen or fluorine atom, a hydroxy, methyl or methoxy group, R 4 in the above formulas means an alkyl group with 1 to 4 carbon atoms,

or R a group of the general formula III

where one of the residues R2 or R3 means a hydroxy group, and the other of these residues means a group with the formulas

or both residues R 2 and R 2 mean the group -CONH 2 , or

b) A means a p-hydroxyphenyl group and

R the group with the general formula II where n is 0 or 1,

and R,, if n is 0, means the groups with the formulas

-S02-R5, -S02-NH-R4, -S02-N(R4)2 or the group -S02"NH2 in the meta position, and if n is 1, R^ means the above-mentioned groups and furthermore a fluorine atom, a-hydroxy group, a nitro group, the group H2NC0-, the groups -S0-CH3, -S02~CH3 or p-H2N-SO2-, or a methyl or methoxy group, where R4 in the above formulas is as indicated above, and R,- means an alkyl group with 2 to 4 carbon atoms, or R a group of the general formula III where one of the residues R2 or R^ means a hydroxy group, and the other of these residues means a group of the formulas -SO^-NH^,

or both residues R 2 and R 2 mean

the group -C0NH2, or

c) A means a 2-thienyl group, a cyclohexa-1,4-dien-1-yl group, a 3,4-dihydroxyphenyl or a 3-chloro-4-hydroxyphenyl group, and

R a group of the general formula II where n is 0 or 1, and R^means a fluorine atom > a methyl or methoxy group or a group of the formulas

-S02-R4, -S02-NH2, -S02-NH-R4 or -S02~N(R4)2, R4 in these formulas being as indicated above, and R^ can also be a hydrogen atom if A means a 2-thienyl -, 3,4-dihydroxyphenyl or 3-chloro-4-hydroxyphenyl group, or R^ can be a hydroxy group or a methylcarbonyloxy group if A means a 2-thienyl group, a cyclo-

hexa-1,4-dien-1-yl group or a 3-chloro-4-hydroxyphenyl group, or

R a group of the general formula III where R,, means a hydroxy group and R^ a hydroxy group or groups

-CONH2, -CO-NHCH3, -SC>2-NH2, or both radicals R2 and R^ can also simultaneously mean the group -CONH2. Such connections with the general are preferred formula I where R denotes the groups with the formulas It has been shown that particularly valuable are such compounds of the general formula I where R denotes the group

and A a -phenyl-, 2-thienyl-, 3-chloro-4-hydroxyphenyl- or a 3,4-dihydroxy-phenyl group, the R group

and A a phenyl, p-hydroxyphenyl, 2-thienyl, 3-chloro-4-hydroxyphenyl or 3,4-dihydroxyphenyl, or the R group

and A a phenyl or

p-hydroxyphenyl group.

The penicillin compounds of the general formula I

can exist in two tautomeric forms (namely lactim- and lactam-type). It is particularly dependent on the relevant solvent and the nature of the substituent R, which of the two forms I or I' predominates:

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

With respect to the chirality center C, the compounds of the general formula I can exist in both the possible R and S configurations, and also as a mixture of these two configurations. Particular preference is given to such compounds which have a D=R configuration.'

The new semi-synthetic penicillins with the general formula I show a broad spectrum of action against gram-positive and gram-negative bacteria and have a very good compatibility in

human beings.

As is known, penicillin antibiotics inhibit the growth of various gram-positive and gram-negative bacteria. It is also known that only a few penicillins have a good effect against important gram-negative harmful bacteria, which particularly occur in hospitals, such as Pseudomonas and Klebsiella. In recent years, however, there has been an increasing occurrence of infections caused by these bacteria, particularly Pseudomonas species. Penicillin derivatives such as carbenicillin (US patent 3,142,673), sulbenicillin (US patent 3,660,379)

and ticarcillin (US patent 3,282,926) are indeed described as antipseudomonal antibiotics, but both in vitro and in vivo show only a moderate effect. An important further development is acylated derivatives of cc-amino-benzyl penicillins, e.g. ampicillin and amoxycillin. From these classes of compounds, which in recent years have been intensively processed, azlocillin = 6-(D-a-[(2-oxo-imidazolidin-l-yl)-carbonylamino]-4-phenylacetamido)-penicillanic acid has recently been found sodium salt (eg, Belgian patent-767,647) as another antipseudomonas penicillin. However, for a successful treatment, this penicillin must be administered in large doses. Moreover, its activity against Klebsiella and E.coli species is only moderate. There has thus been a further need to find new penicillins that have an enhanced effect against bacteria such as Psudomonas resp. Klebsiella and E. coli.

While, as mentioned, acyl derivatives of α-amino-benzylpenicillins have been intensively researched and are still being researched, little is known about derivatives where a heterocyclic group is connected via a ureido bridge (NHCNH-)

to the α-benzyl carbon atom in α-aminobenzylpenicillins.

Admittedly, hydroxypyridylureido-benzyl penicillins with the general formula IV are described in German official documents 2,450,668 and 2,535,655 and US patent 4,031,230:

These compounds, however, with regard to their antibacterial activity are clearly inferior to the compounds according to the widely available European patent application 79 100 468.2, which differ from the compounds produced according to the invention, only by other meanings of the residue R and by other combinations of the residues A and R.

However, the new compounds produced according to the invention have better activities compared to the compounds according to this European patent application against harmful microorganisms, especially bacteria, such as E. coli, Pseudomonas and Klebsiella.

The compounds with the general formula I can be prepared as follows: 1) By reacting a compound with the general formula formula V

where A is as indicated above, with a pyrimidine derivative of the general formula VI

where R is as indicated above, and B means the group -NCO or a reactive derivative of the group NHCOOH, such as, for example, the groups -NHC0C1, -NHCOBr or

the group NHC0Cl being particularly preferred. It is also possible to use mixtures of such pyrimidine derivatives with the general formula VI where B partly has one and partly the other of the above meanings, e.g. the groups

simultaneously next to each other.

The starting compounds of the general formula V can

used in the form of their inorganic or organic salts,

e.g. such as triethylammonium salt or sodium salt. The reaction can be carried out in suitable mixtures of water and 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, dimethyl sulfoxide or alcohols such as isopropanol or in hexametapol. Below this, the pH value of the reaction mixture is kept by adding bases or by using buffer solutions in a pH range from approx. 2.0 to 9.0, preferably between pH 6.5 and 8.0. However, it is also possible to carry out the reaction in anhydrous, organic solvents, e.g. halogenated hydrocarbons such as chloroform or methylene chloride, with the addition of bases, preferably triethylamine, diethylamine or N-ethylpiperidine.

Furthermore, the reaction can be carried out in a composition of water and a non-water-miscible solvent such as ethers, e.g. diethyl ether, halogenated hydrocarbons, e.g. chloroform or methylene chloride, carbon disulphide, ketones, e.g. isobutyl methyl ketone, esters, e.g. acetic acid ethyl ester, aromatic solvents, e.g. benzene, as it is appropriate to stir vigorously and to keep the pH value 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 one as starting materials for the procedure

use the silyl derivatives of the compounds of the general formula V (e.g. the mono- or di-trimethylsilyl derivatives) and react them with compounds of the general formula VI, one usually conveniently works in water- and hydroxyl group-free solvents, e.g. . in halogenated hydrocarbons such as methylene chloride or chloroform, benzene, tetrahydrofuran, acetone or dimethylformamide, etc. The addition of bases is not necessary here, but can in some cases be beneficial 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.

Instead of the silyl esters, all other carboxyl derivatives of α-amino-benzylpenicillins, which are known in connection with the production of semi-synthetic penicillins, can also be used. Typical examples are the trityl esters, the p-nitrobenzyl esters or the phenacyl esters. In connection with sales, these derivatives can be converted into the new penicillins by known methods. The quantity of the bases used is determined, e.g. on the basis of a specific pH value to be maintained. When a pH measurement and 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 of base are used for the non-silylated compounds of the general formula IV. When using silylated compounds, preferably up to one 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 and heterocyclic bases . E.g. mention may be made of sodium, potassium and calcium hydroxide, calcium oxide, sodium and potassium carbonate, sodium and potassium hydrogen carbonate, ethylamine, methylethylamine, triethylamine, hydroxyethylamine, aniline, 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. phos fat buffers, citrate buffers and tris-(hydroxymethyl)-amino-methane buffers.

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

The reaction components with the general formulas IV and V can be readily reacted with each other in equimolar amounts. 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) When reacting ureidocarboxylic acids with the general formula VII

where A and R have the meanings given above, their salts or reactive derivatives, with 6-amino-penicillanic acid of formula VIII

or its inorganic or organic salts or derivatives which can be readily converted to 6-aminopenicillanic acid. That thereby

formed reaction product can optionally then be hydrolyzed or catalytically hydrogenated to a penicillin with the general formula I.

As reactive derivatives of the ureidocarboxylic acids with the general formula VII, e.g. are used their acid anhydrides such as those that can be derived from chloroformate esters, e.g. chloroformate ethyl or isobutyl ester, or their reactive esters, such as the p-nitrophenyl esters or the N-hydroxy-succinimide 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 Ø-lactam chemistry.

The 6-aminopenicillanic acid is advantageously used in the form of

one of its derivatives. As derivatives, there are e.g. namely: its trimethylsilyl ester, trityl ester, p-nitrobenzyl ester, phenacyl ester or its 0,N-bis-trimethylsilyl derivative. These derivatives are preferably reacted in an aprotic solvent such as methylene chloride or tetrahydrofuran. One can also use the 6-aminopenicillanic acid in the form of its salts, e.g. its triethylammonium salt, and one uses here e.g. methylene chloride or a protic solvent or an aqueous medium or an aqueous-organic solvent such as tetrahydrofuran-water mixtures.

The ureidocarboxylic acids, their salts or their reactive derivatives are reacted with the 6-aminopenicillanic acid or its derivatives in a solvent at temperatures between -40 and • +40°C, possibly in the presence of a base. If e.g. an anhydride of the ureidocarboxylic acid, e.g. the anhydride with ethyl chloroformate, is reacted with a derivative of 6-aminopenicillanic acid, the reaction is carried out while cooling, e.g. at -10 to +10°C in the presence of a tertiary amine such as triethylamine or N>N-dimethylaniline,

in a solvent such as acetone, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane, hexametapol or in a mixture of these solvents. If you e.g. reacts an N-hydroxysuccinimide ester of the ureidocarboxylic acid with the 6-amino-penicillanic acid, 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 VII itself or its salts with 6-amino-penicillanic acid or with its salts is advantageously carried out in the presence of a condensing agent, e.g. in the presence of N,N<1->dicyclohexy1-carbpdiimide.

If a derivative of 6-aminopenicillanic acid is used, e.g. one of its above-mentioned esters, depending on the reaction conditions, a reaction product such as e.g. still contains the ester function. However, such a reaction product can easily be transferred to the penicillin with the general formula I. If, for example, the carboxyl group in the 6-aminopenicillanic acid is present in the form of its silyl ester, after the reaction it can also be present in the form of its silyl ester in the obtained penicillin with the general formula I. In this case, this silyl ester group is de-hydrolyzed after the actual reaction, whereby the compound is obtained with the general formula I. In other cases, e.g. when a p-nitrobenzyl ester is present, this p-nitrobenzyl ester group is split off after the actual reaction, whereby penicillins with the general formula I are obtained.

The processing of the reaction mixture obtained by both methods after completion of the reaction is carried out according to methods that are common for 3-lactam antibiotics, and the same applies to the isolation and purification of the end products, e.g.

for the liberation of the acid from its salts and the transfer of the free acid to other salts by means of inorganic or organic bases. For the preparation of the potassium or sodium salts, it is particularly appropriate to precipitate these salts from an alcoholic-etheric solution of the free acid by adding potassium or sodium 2-ethylhexanoate.

The compounds of the general formula V used as starting materials are known from the literature, see e.g.

E. H. Flynn, Cephalosporines and Penicillines, Academic Press, New York and London (1972).

The starting materials with the general formula VI can e.g. are prepared by reacting the appropriate 5-aminopyrimidines of the general formula IX

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 formed hydrogen chloride using equimolar amounts of an inert, organic base such as triethylamine or pyridine. As a solvent, pyridine can also be used in excess. If the relevant aminopyrimidines with the general formula IX should be poorly soluble in one of the mentioned solvents, the phosgenation can also be carried out in a heterogeneous phase. Furthermore, the aminopyrimidines of the general formula IX can, by treatment with a silylating agent such as hexamethyldisilazane or trimethylchlorosilane/triethylamine or N,O-bistrimethylsilylacetamide, be transferred to a usually in the mentioned solvents very easily soluble, single or, according to the exchangeable hydrogen atoms present, polysilylated aminopyridine, which then reacts with phosgene to give the corresponding compounds of the general formula VI. 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 VI can also partially or completely exist as a dihydro-oxazolo-pyrimidine with the general formula Via isomeric with the isocyanates

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

The starting compounds with the general formula VI or mixtures thereof are usually well soluble in the above-mentioned solvents and, after removal of excess phosgene, can be reacted directly with the appropriate penicillin derivatives of the general formula V without further purification.

However, it is also possible to isolate the intermediate with the general formula Via, optionally desilylate it with a protic solvent, e.g. water or methanol,

purify it on the basis of its solubility properties and react it in the manner described above.

The preparation of the 2-substituted 5-amino-4-hydroxy-pyrimidines of the general formula IX is, to the extent that they are not already described in the generally available European patent application 7 9 100 468.2, described in more detail in the following examples. Particularly suitable is the reaction of 2-chloro-4-hydroxy-5-nitro-pyrimidine with anilines or benzylamines in aqueous solution, the nitro group being then reduced by known methods, or reaction of 5-benzoylamino-4-hydroxy-2-methylmercaptopyrimidine with the suitable anilines or benzylamines in melt or in a high-boiling solvent such as sulfolane.

The ureidocarboxylic acids of the general formula VII can be easily obtained by reacting pyrimidine derivatives of the general formula VI with glycine derivatives of the general formula X where A is as indicated above. The turnover takes place at temperatures between -20 and +40°C, preferably between 0 and +20°C,

in a solvent. As solvents, e.g. mixtures of water and organic solvents which are miscible with water are used, e.g. acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, ethanol or dimethylsulfoxide. If necessary, it is necessary to use a hydrogen-halide binding agent, and suitable such agents are e.g. trialkylamines such as triethylamine, or inorganic bases such as dilute caustic soda.

It has been found that the compounds of the general formula I possess valuable pharmacological properties with good compatibility. The new active substances can thus be used for prevention and chemotherapy of local and systemic infections in human and animal medicine. As diseases that can be prevented or can be healed with the help of the new compounds, e.g. those in the respiratory tract, oral cavity and urinary tract are mentioned. The compounds are particularly effective against pharyngitis, pneumonia, peritonitis, pyelonephritis, otitis, cystitis, endocarditis, bronchitis, arthritis and common systemic infections. Furthermore, these compounds can be used as substances for the preservation of inorganic or organic materials, in particular of organic materials such as polymers, lubricants, paints, fibres, leather, paper and wood as well as foodstuffs.

This is made possible by the fact that the compounds of the general formula I both in vit ro. and in vivo works very strongly against harmful microorganisms, especially against gram-positive and gram-negative bacteria and bacteria-like microorganisms, and they are particularly distinguished by a broad spectrum of effects. Moreover, after parenteral administration, the compounds of the general formula I show high levels in tissues, serum, organs and in the urine.

In the following table 1, typical ones are indicated, in particular

active penicillins produced according to the invention. The aforementioned penicillins can be prepared according to methods 1 or 2. These are compounds of the general formula I where A and R are defined as follows:

With these penicillin derivatives, one can e.g. treat and/or prevent local and/or systemic diseases caused by the following microorganisms or by mixtures thereof: Micrococcaceae, such as Staphylococci;

Lactobacteriaceae, such as Streptococci;

Neisseriaceae, such as Neisseries;

Corynebacteriaceae, such as Coryne bacteria;

Enterobacteriaceae, such as Escherichiae bacteria of the Coli group, Klebsiella bacteria, e.g. K. pneumoniae;

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 Brucellaceae, such as Pasteurella bacteria; Brucella bacteria, e.g. Brucella abortus; Haemophilus bacteria, e.g. Haemophilus influenzae; Bordatella bacteria, e.g. Bordetella pertussis;

Moraxella bacteria, e.g. Moraxella lacunata;

Bacteroidaceae, such as Bacteroides bacteria;

Fusiform bacteria, e.g. Fusobacterium fusiforme; Sphaerophorus bacteria, e.g. Sphaerophorus necrophorus; Bacillaceae, such as aerobic spore formers, e.g. Bacillus anthracis; anaerobic spore formers-Chlostridia, e.g. Clostridium perfringens; Spirochaetaceae, such as Borrelia bacteria;

Treponema bacteria, e.g. Treponema pallidum;

Leptospira bacteria, sp such as Leptospira interrogans.

The above list of microorganisms is only

examples and shall not represent any limitation.

The action of the penicillins prepared according to the invention

can e.g. is demonstrated by the following investigations:

1. In vitro experiments

For the investigations, the method was a serial dilution test

1 microtiter system used. The examination of the compounds with regard to bacteriostasis was carried out in liquid medium. The bacteriostasis effect was investigated at the following concentrations: >64, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.05, 0.03, 0.015 and 0.007Mg/ml . A nutrient medium with the following composition was used:

10 g peptone, i g meat extract oxoid, 3 g sodium chloride,

2 g sec. sodium phosphate is diluted with distilled water to 1000 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 diameter 14 mm, filter 546 nm) on the basis of the turbidity of a barium sulfate comparison suspension obtained with a barium sulfate slurry prepared by adding 3.0 ml l % barium chloride solution was added to 97 ml of 1% sulfuric acid. After the setting, Streptococcus Aronsen 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 was 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 1 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 effective concentration) was obtained.

The following organisms were used as test organisms:

Staphylococcus aureus SG 511, Escherichia coli ATCC 11 775, Pseudomonas aeruginosa Hamburgensis and Walter, Serratia marcescens ATCC 13 880, Klebsiélla pneumoniae ATCC 10 031 and BC 6, Proteus mirabilis Hamburgensis, Proteus rettgeri BC 7 and Enterobacter cloacae ATCC 13 047.

In the following table 2, the minimum inhibitory concentrations (MIC) found for typical representatives of the new compounds are indicated, where the numbering corresponds to that used in table 1.

A number of the new compounds were investigated in vivo

in experimental infections of mice. E. coli ATCC 11775 and Pseudomonas aeruginosa Walter were used as pathogenic bacteria. An intraperitoneal infection was induced with

0.2 ml of a 5% mucin suspension of the bacteria. This corresponds to approx. 2 x 10 6 E. coli bacteria, resp. 8 x 10 5 Pseudomonas bacteria per 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 to determine the ED^q (dose where

.50% of the animals survived). In the case of the E. coli infection, treatment was taken once. In the case of the Pseudomonas infection, treatment was carried out three times.

The observation period was 7 days in both cases. The results from these experiments with representative penicillins produced according to the invention are given in table 3.

As comparison compounds, the known penicillins with the general formula served

with

R = H : Azlocillin = A

R = SO 2 CH 3 : Mezlocillin = B

further

D-α-[(4-hydroxy-3-pyridyl)-ureido]-benzylpenicillin sodium

(see German official document 2.450.668) = C

and

piperacillin (T 1220) = D

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

LD,-Q is the dose which causes 50% of the animals to die within 8 days of administration. All compounds show an LD^^ of over 4 g/kg when administered orally, and an LD5q of over 3 g/kg when administered subcutaneously, i.e. at 3 g/kg no animals died, and the compounds are thus practically non-toxic.

The stated values show that representative penicillins produced according to the invention, due to their broad antibiotic spectrum, their high antibacterial activity, their low toxicity and their high serum level after subcutaneous and oral administration, are valuable antibiotics.

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, dragees, capsules, granules, suppositories, solutions, suspensions, emulsions, ointments, gels, creams, powders and spray preparations. Advantageously, the active ingredient or a mixture of different active ingredients with the general formula I is administered in human or veterinary medicine, in a dosage between 5 and 500, preferably 10-200 mg/kg body weight per 24 hours, possibly in the form of several individual administrations. A single administration contains the active ingredient or active ingredients in quantities of preferably approx. 1 to approx. 100, especially 5 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 degree of the disease, the nature of the preparation and the form of administration of the medicine, and also the time period or 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 optimal dosage and form of administration required at all times for the active substance can easily be carried out by any professional on the basis of his professional knowledge.

For parenteral administration, it is preferred to dissolve

the new penicillin compound in a non-toxic liquid medium for injection purposes and to inject the solution intramuscularly, intravenously or subcutaneously.

It is also possible to dissolve the new penicillin compound

in a non-toxic, liquid medium or in an ointment base or mixing it with this and applying the solution or mixture directly to the damaged area. The compounds can also be used as suppositories after mixing with a base for suppositories or after dissolution therein.

Examples of non-toxic, liquid media that can be used

for the manufacture of injectable preparations containing the penicillin compound as active ingredient, are sterilized, deionized water, physiological saline solution, glucose solution for injection, Ringer's solution or amino acid solution for injection.

The penicillin compound can also be dissolved in other injectable preparations and administered parenterally.

For oral administration, the new penicillin compounds are used in the form of a pharmaceutical preparation containing the compound(s), possibly mixed with pharmaceutically compatible carriers, e.g.

an organic or inorganic, solid or liquid excipient, which is suitable for oral administration. Optionally, these preparations may also contain excipients, stabilizers and other commonly used additives.

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

The following examples shall serve to illustrate the invention further (the indications of Rf values apply to the system n-butanol-water-glacial vinegar = 60:25:15, SiO2~plate).

By "ampicillin" is meant α-aminobenzylpenicillin, by "amoxycillin" is meant α-amino-p-hydroxy-benzylpenicillin and by "epicillin" is meant α-amino-α-(1,4-cyclohexadien-1-yl)- methylpenicillin which has D=R configuration in the side chain.

I. Preparation of the starting compounds

Example A

5- amino- 4- hydroxy- 2- p- methylsulfonyl anilino- pyrimidine

Dissolve 3.2 g (0.019 mol) of 4-methylthio-nitrobenzene in 20 ml of formic acid and add 0.05 mol of hydrogen peroxide as a 30% solution at room temperature. The solution is thereby heated.

After standing for 1 hour at room temperature, precipitation is carried out with ice water, the precipitate is suctioned off and dried at 50°C in a vacuum. 2.9 g (76.2% of the theoretical) of p-nitrophenylmethylsulfone are obtained.

3.42 g (0.017 mol) of p-nitrophenyl-methyl-sulfone are dissolved in 100 ml of methanol and hydrogenated in the presence of 1 g of Raney nickel at 50°C and 5 bar. The solution is filtered from the catalyst and evaporated to dryness. The residue is dissolved in 40 ml of dioxane and a solution of 3.77 g (0.0175 mol) of 2-chloro-4-hydroxy-5-nitro-pyrimidine sodium salt • lf^O in 120 ml of water is added. The solution is heated on a steam bath for 3 hours. After cooling, the deposited precipitate is suctioned off, washed with water and dried at 50°C in a vacuum.

Yield: 3.1 g (58.7% of theory) 4-hydroxy-2-p-methyl-sulfonylanilino-5-nitropyrimidine.

3.3 g (0.01063 mol) of 4-hydroxy-2-p-methylsulfonyl anilino-5-nitropyrimidine are dissolved in 50 ml of water while heating by adding 6 ml of concentrated ammonia. While stirring, 7.83 g (0.045 mol) of sodium dithionite are added all at once. Then stir for a further 15 minutes at 60°C. After cooling, the formed precipitate is suctioned off, washed with water and dried at 50°C in a vacuum.

Yield: 2.4 g (80.6% of theory) 5-amino-4-hydroxy-2-p-methylsulfonyl anilino-pyrimidine.

NMR spectrum (DMSO + CD30D) signals at ppm: 3.15 (s, 3H),

7.2 (s, 1H), 7.8 (broad s, 4H).

Example b

5- amino- 4- hydroxy- 2- p- methylsulfinyl anilino- pyrimidine

3.8 g (0.014 mol) of 4-hydroxy-2-p-methylthio-anilino-5-nitro-pyrimidine are suspended in 50 ml of glacial acetic acid, 2.3 g (0.02 mol) of 30% hydrogen peroxide are added and heated under stirring for 10 minutes on a steam bath. After cooling, the formed precipitate is suctioned off and dried in a vacuum.

Yield: 2.28 g (55% of theory) 4-hydroxy-2-p-methyl-sulfinylanilinino-5-nitro-pyrimidine.

2.1 g (0.0079 mol) of 4-hydroxy-2-p-methylsulfinylanilinino-5-nitropyrimidine are suspended in 60 ml of water and dissolved by adding 7 ml of concentrated ammonia and heating. 8 g of sodium dithionite are added at once, and the solution is heated for 20 minutes on a steam bath. After cooling, the solution is brought to pH 7 with glacial acetic acid and allowed to stand for several hours in a refrigerator.

After extraction, the crude product is purified by chromatography over a silica gel column (eluent chloroform/methanol 5:1). Yield: 0.8 g (38.2% of the theoretical).

NMR spectrum (DMSO + CD 3 OD) signals at ppm: 2.75 (s, 3H), 7.15 (s, 1H), 7.7 (q, 4H).

Starting from the suitably substituted aniline and 4-hydroxy-2-p-methylthio-anilino-5-nitro-pyrimidine resp. 2-chloro-4-hydroxy-5-nitropyrimidine and subsequent reduction, the pyrimidines indicated in the following table were synthesized in an analogous manner.

Pyrimidines of the general formula

Pyrimidines of the general formula

Pyrimidines of the general formula I

Example C

D- L- g-[ 3-( 4- hydroxy- 2- p- methylaminosulfonYlanilino- 5- pyrimidinyl)-ureido]- thienylacetic acid

2.95 g (0.01 mol) of 5-amino-2-p-methylaminosulfonyl anilino-4-hydroxy-pyrimidine are heated under reflux for 30 minutes in 100 ml of dry tetrahydrofuran together with 6 g of trimethylsilyldiethylamine. It is then evaporated to dryness in vacuo, and the solid product is dissolved in 60 ml of dry tetrahydrofuran under nitrogen. This solution is added dropwise under ice-cooling to 1.05 g of phosgene, dissolved in 50 ml of tetrahydrofuran.

You continue to stir for 5 minutes at room temperature and evaporate to approx. half volume in vacuum. This solution is added dropwise under ice-cooling to 1.57 g (0.01 mol) D,L-thienylglycine,

which was dissolved with 1N caustic soda in a mixture of 50 ml of tetrahydrofuran and 20 ml of water. At the end of the addition, the pH value is set to 8.0. The mixture is stirred for 1 hour at room temperature, the tetrahydrofuran is evaporated in vacuo, some water is added and the mixture is decanted twice with ethyl acetate at pH 7.0.

The aqueous phase is then adjusted to pH 2.7 with 2N hydrochloric acid. The precipitated product is suctioned off and dried.

Yield: 3.3 g (69%) .

IR spectrum: 3300, 1660, 1555 cm<-1>.

NMR spectrum (DMSO + CD30D) signals at ppm:

2.45 (s, 3H), 5.50 (s, 1H), 7.05 (m, 2H), 7.40 (m, 1H), 7.80

(q, 4H), 8.35 (s, 1H).

Analogously, the following ureidocarboxylic acids were synthesized: a) ureidocarboxylic acids with the general formula b) ureidocarboxylic acids with the general formula c) ureidocarboxylic acids with the general formula

II Production of the final products

Example 1

D- a-[ 3-( 4- hydroxy- 2- p- methylaminosulfonyl anilino- 5- pyrimidinyl)-ureido]- p- hydroxy- benzylpenicillin- sodium

1.47 g (0.005 mol) of 5-amino-4-hydroxy-2-p-methylaminosulfonyl anilino-pyrimidine is suspended in 50 ml of dry tetrahydrofuran and heated under reflux together with 4 g of trimethylsilyldiethylamine until complete dissolution (10 to 30 minutes). The solution is evaporated to dryness in vacuo, taken up again in 50 ml of tetrahydrofuran and added dropwise under ice-cooling to a solution of 530 mg of phosgene in 35 ml of dry tetrahydrofuran. Stirring is continued for 10 minutes at room temperature and then evaporated in a vacuum to approx. half volume.

2.1 g (0.005 mol) of amoxicillin are suspended in a solvent mixture of 40 ml of tetrahydrofuran and 10 ml of water. Under ice-cooling, triethylamine is added to the solution.

The solution prepared above is added dropwise to this solution, keeping the pH value at approx. 7.0 when triethylamine is added. 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 penicillin is suctioned off

and dried in a vacuum.

By adding the calculated amount of sodium ethyl hexanoate in methanol, the sodium salt is prepared and precipitated with ether. Yield: 2.16 g (62%);

IR spectrum: 1765, 1650, 1610 cm"<1>;

NMR spectrum (DMSO + CD30D) signals at ppm: 1.55 (d, 6H),

2.55 (s, 3H), 4.05 (s, 1H), 5.45 (d + s, 3H), 6.75 (d, 2H),

7.30 (d, 2H), 7.85 (q, 4H), 8.35 (s, 1H).

By this method, the penicillins with the following formula were synthesized:

Example 50

D, L- g-[ 3-( 2- p- aminosulfonyl anilino- 4- hydroxy- 5- pyrimidinyl)-ureido]- 2- thienylmethy1-penicillin- sodium

Add 0 .52 g (5.1 mmol) of N-methylmorpholine and cooled to -20 to 25°C. To the mixture is added 0.54 g (5 mmol) chloroformic acid ethyl ester dissolved in 20 ml of methylene chloride, and the mixture is stirred for 45 minutes at -20°C (Solution A).

To a suspension of 1.1 g (5 mmol) 6-aminopenicillanic acid

3.1 g (30 mmol) of triethylamine are added dropwise to 50 ml of methylene chloride, then stirred for 1-2 hours at room temperature until a solution is obtained, and finally cooled to -20°C (solution B).

Solution B is added to solution A, while the temperature is kept at -20°C, and the reaction mixture is allowed to react further for 45 minutes at -20°C and 2 hours at room temperature.

150 ml of water are then added, the pH value of the aqueous phase is adjusted to 7.2, the organic layer is separated, and the aqueous phase is extracted 3 times with ethyl acetate. The ethyl acetate extract is discarded. The aqueous phase is covered with a layer of ethyl acetate and its pH is adjusted to 3.0 by adding 2N hydrochloric acid. The organic layer is separated, dried with sodium sulphate and evaporated. The penicillin obtained is dissolved in methanol and the sodium salt is precipitated by adding an equimolar amount of sodium ethyl hexanoate.

Yield: 2.9 g (84% of the theoretical),

IR spectrum: 1760, 1655, 1600 cm"<1>,

NMR spectrum (DMSO + CD30D) signals at ppm:

1.55 (d, 6H), 4.0 (s, 1H), 5.45 (m, 3H), 7.1 (m, 2H), 7.45

(m, 1H), 7.85 (q, 4H), 8.35 (s, 1H).

According to the procedure in example 50, the following penicillins were synthesized: a) with the formula b) with the formula c) with the formula

The compounds with the general formula I and I' can be incorporated into the usual pharmaceutical application forms as

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 (2)

1. Analogy method for the preparation of new antibacterial penicillins with the general formulas respectively where A and R have the following meanings: a) A means a phenyl group and R means the group of the general formula II where n is 0 or 1, and R^ , if n is 0, means the groups -S02 -R4 , -S0-R4 , -S02 -NH2 , -S02~NHR4 or -S02" N(R4 )2 , and, if n is 1, R^ represents the above groups and in addition a hydrogen or fluorine atom, a hydroxy, methyl or methoxy group, where R4 in the above formulas means an alkyl group with 1 to 4 carbon atoms, or R represents a group of the general formula III where one of the residues R 2 or R 2 means a hydroxy group, and the other of these residues means a group of the formulas or both radicals R2 and R^ mean the group -CONH2 , or b) A means a p-hydroxyphenyl group, and R means the group of the general formula II where n is 0 or 1, and R,, if n is 0, means the groups with the formulas -S02 -R5 , -S02~ NHR4 , -S02 -N(R4 )2 or the group -S02-NH2 in the meta position, and if n is 1, R^ means the above-mentioned groups and also a fluorine atom, a hydroxy group, a nitro group, the group H2 NC0-, the groups -SO-CH3, -SO2"CH3 or p-H2 N-SO2~, or a methyl- or methoxy group, R 4 in the above formulas being as indicated above, and R 1 - means an alkyl group with 2 to 4 carbon atoms, or R means a group of the general formula III where one of the residues R2 or R3 means a hydroxy group, and the other of these residues means a group of the formulas -SO2~NH2, or both residues R2 and R3 mean the group -CONH2 , or c) A means a 2-thienyl group, a cyclohexa-1,4-dien-1-yl group, a 3,4-dihydroxyphenyl- or a 3-chloro-4 -hydroxyphenyl group, and R means a group of the general formula II where n is 0 or 1, and is a fluorine atom, a methyl or methoxy group or a group of the formulas S02 -R4 , -S02 -NH2 , -S02 -NHR4 or -S02" N(R4 )2 , R4 in these formulas being as indicated above, and R^ can also be a hydrogen atom if A means a 2-thienyl-, 3,4-dihydroxyphenyl or 3-chloro-4-hydroxyphenyl group, or R^ can be a hydroxy group or a methylcarbonyloxy group if A means a 2-thienyl group, a cyclohexa-1,4-dien-l-yl group or a 3-chloro -4-hydroxyphenyl group, or R means a group of the general formula III where R2 means a hydroxy group, and R^ means a hydroxy group or the groups -CONH2, -CO-NHCH3 or -SO2 -NH2, or both residues R2 and R^ can also simultaneously mean the group -CONH2 , and their salts with inorganic or organic bases, characterized by ata) a compound of the general formula V where A is as indicated above, is reacted with a pyrimidine derivative of the general formula VI where R is as stated above, and B means the group -NCO or a reactive derivative of this group or the groups -NHC0C1, -NHCOBr or or with mixtures of such pyrimidines of the general formula VI where B partly has one and partly the other of the meanings indicated above, in a solvent and a pH range between 2.0 and 9.0 at temperatures between -20 and +50°C, orb) a ureidocarboxylic acid of the general formula VII where A and R have the meanings given above, or its salts or reactive derivatives, are reacted with 6-amino-penicillanic acid of formula VIII or with its inorganic or organic salts or with its derivatives which can easily be transferred to the 6-aminopenicillanic acid, between -40 and +40°C in the presence of a solvent and optionally a base, and/or a thus obtained compound with the general formula I or I' is transferred to its salts with inorganic or organic bases. 2. Process as set forth in claim 1, characterized in that D-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido]-benzylpenicillin sodium, D,L-a-[3-( 2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido]-2-thienylmethyl-penicillin sodium, D,L-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido ]-m,p-dihydroxy-benzylpenicillin sodium, D,L-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido]-m-chloro-p-hydroxy-benzylpenicillin sodium, D-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido]-1,4-cyclohexadien-1-yl-methylpenicillin sodium, D-a-[3-(4-hydroxy-2-p-methylaminosulfonyl anilino-5-pyrimidinyl)-ureido]-p-hydroxy-benzylpenicillin sodium, D-α-[3-(4-Hydroxy-2-p-methylaminosulfonyl anilino-5-pyrimidinyl)-ureido]-benzylpenicillin sodium, D,L-a-[3-(4-hydroxy-2-p-methylaminosulfonyl anilino-5-pyrimidinyl)-ureido]-m-chloro-p-hydroxy-benzylpenicillin sodium, D-a-[3-(4-hydroxy-2-p-methylsulfinylanilinino-5-pyrimidinyl)-ureido]-benzylpenicillin sodium, D,L-a-[3-(4-hydroxy-2-p-methylsulfinylanilinino-5-pyrimidinyl)-ureido]-m-chloro-p-hydroxy-benzylpenicillin sodium, D-a-[3-(2-(p-aminosulfonyl-m-hydroxy-anilino)-4-hydroxy-5-pyrimidinyl)-ureido]-p-hydroxy-benzylpenicillin sodium or D-a-[3-(2-(p -aminosulfonyl-m-hydroxy-anilino)-4-hydroxy-5-pyrimidinyl)-ureido]-benzylpenicillin sodium.