GB2086904A - Penicillin derivatives - Google Patents

Description

SPECIFICATION Penicillin derivatives This invention relates to new pencillins, to processes for their preparation, to compositions containing them and to methods for using them. According to one feature of the present invention there are provided compounds of general formula I,

and their tautomers of general formula I'

wherein either a) A represents a phenyl group and R represents a group of formula II,

[in which n is 0 or 1 and R, represents the group -NH-CO-NH2; -NO2; -CO-NH2; -CO-NHCH3; -CO-N(CH3)2; -0-CO-CH3; -SO2-R4; -SO-R4; -S02-NH2; -SO2-NH-R4 or-SO2 N(R4)2 (where R4 represents an alkyl group with 1 to 4 carbon atoms) or, when n is 1, alternatively a hydrogen or fluorine atom or a hydroxy, methyl or methoxy group]; or R represents a group of formula III

(in which one of R2 and R3 represents a hydroxy group and the other represents a group of formula -SO27-NH2; -CO-NH2; or CO-NH-CH3 or both group R2 and R3 each represent the group -CONH2);or b) A represents a hydroxyphenyl group and R represents a group of formula II as defined above [in which n is 0 or 1 and R1 represents the group -NH-CO-NH2; -CO-NH-CH3; CO-N(CH3)2; -O-CO-CH3; -SO-R5; -SO2-R5; SO2-NH-R4; -S02-N(R4)2 or -S02-NH2 (where R4 is as defined above and R5 represents an alkyl group with 2 to 4 carbon atoms), or when n is 1, alternatively a fluorine atom, a hydroxy group, a nitro group, a group H2NCO-, a group -SO-CH3, -S02-CH3 or p-H2N-SO2-, or a methyl or methoxy group, with the proviso that, when n is 0 and R, represent the group SO2NH2, R, is in the meta position] or R represents a group of formula III (in which one of the groups R2 and R3 represents a hydroxy group and the other represents a group of formula -SO2-NH2; -CO-NH2; -CO-NH-CH3 or both groups R2 and R3 each represent a group -CONH2);or c) A represents a 2-thienyl, cyclohexa-1,4-dien-1-yl, 3,4-dihydroxyphenyl or 3-chloro-4hydroxyphenyl group and R represents a group of formula II as defined above [in which n is 0 or 1 and R1 represents a hydrogen of fluorine atom, a methyl, methoxy hydroxy or acetoxy group or a group of formula H2N-CO-NH-; H2N-CO-; CH3-NH-CO-;(CH3)2N-CO; -SO-R4; -SO2-R4; SO2 NH2; SO2 NH R4 or -SO2-N(R4)2 (where R4 is as defined above) with the proviso that R, may only represent a hydrogen atom, when A represents a 2-thienyl, 3,4-dihydroxyphenyl or 3-chloro-4hydroxyphenyl group and R, may only represent a hydroxy or acetoxy group when A represents a 2thienyl, cyclohexa-1,4-dien-1-yl or 3-chloro-4-hydroxyphenyl group] or R represents a group of formula III as defined above (in which R2 represents a hydroxy group and R3 represents a hydroxy group or a group --CONH2, -CO-NHCH3 or -SO2-NH2 or both groups R2 and R3 may each represent the group -CONH2; and the salts thereof with inorganic or organic bases. The compounds according to the invention possess interesting biological properties and in particular a broad spectrum of activity against both gram-positive and gram-negative bacteria. It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically compatible but other salts may find use, for example, in the preparation of the compounds of general formula I and I' as well as their physiologically compatible salts. Preferred compounds according to the invention are those wherein R represents a group of the formula:

Especially preferred compounds are those wherein either (a) R represents a group

and A represents a phenyl, 2-thieriyl, 3-chloro-4-hydroxy-phenyl or 3,4-dihydroxyphenyl group, or (b) R represents a group

and A represents a phenyl, p-hydroxyphenyl, 2-thienyl, 3-chloro-4-hydroxyphenyl or 3,4dihydroxyphenyl group, or (c) R represents a group

and A represents a phenyl or p-hydroxyphenyl group. Particularly preferred compounds are the following:

. benzylpenicillin. Sodium D-a-[3-(2-p-aminosulfonylamilino-4-hydroxy-5-pyrimidinyl)-ureido]-1,4-cyclohexadien1-yl-methylpenicillin.

benzylpenicillin. Sodium D,L-a-[3-(4-hydroxy-2-p-methylaminosulfonylanilino-5-pyrimidinyl)-ureido]-m-chloro-phydroxy-benzylpenicillin.

benzylpenicillin. The pencillin compounds according to the invention indicated above may be present in two tautomeric forms (namely in the form of the lactim and lactam). Which of the two forms predominates will depend particularly on the solvent used and on the nature of the substituent R. The compounds according to the invention may be present in either the R or S configuration due to the chiral centre denoted C* in the above formulae, as well as in mixtures of these configurations. Compounds having the D=R configuration are particularly preferred. In addition to their broad spectrum of activity against gram-positive and gram-negative bacteria, the new semi-synthetic penicillins according to the invention are very well tolerated in humans. As is known, penicillin antibiotics inhibit the growth of various gram-negative bacteria. It is also known that only a few pencillins show a good activity against major problematical gram-negative pathogens which occur chiefly in hospitals, such as Pseudomonas and Klebsiella. In recent years, however, the incidence of infections caused by these bacteria, particularly by species of Pseudomonas, has risen consistently.Pencillin derivatives such as carbencillin (US Patent Specification No. 3 142 673), sulbenicillin (US Patent Specification No. 3 660 379) and ticarcillin (US Patent Specification No. 3 282 926) are certainly described as antipseudomonaf antibiotics, but they have only a moderate actvity both in vitro and in vivo. An important development is the use of acylated derivatives of a-aminobenzyl penicillins, e.g. ampicillin and amoxicillin. Of these types of compounds, which have been the subject of intensive work in recent years, azlocillin (the sodium salt of 6-{D-alpha -[(2-oxo-imidazolidin-1-yl)-carbonylamino]-4phenylacetamido}-penicillanic acid) (see for example Belgian Patent Specification No. 767 647) has recently been introduced as another pencillin for use against Pseudomonas. However, to ensure successful treatment, this penicillin has to be administered in high dosages.Furthermore, its activity against Klebsiella and E. coli species is only mediocre. There was therefore a need to look for new penicillins having a greater activity against bacteria such as Pseudomonas, Klebsiella and E. coli. Whereas, as already mentioned, there has been and still is intensive research into acyl derivatives of alpha -aminobenzyl penicillins in general, little is known of derivatives wherein a heterocycle is coupled via a ureido bridge

to the a-benzylcarbon atom of a-aminobenzylpenicillins. Only in DE-OS 2 450 668 and 2 533 655 and in US Patent Specification No. 4 031 230 are hydroxypyridylureido-benzylpenicillins of general formula IV described:

However, in their antibacterial activity, these compounds are clearly inferior to the compounds of the earlier published European Patent Application No. 79 100 468.2, which differ from the compounds according to the invention only by the different definitions of the group R or by different combinations of the groups A and R. The compounds according to the invention, however, have even better activities against the problematical pathogens, especially bacteria such as E. coli, Pseudomonas and Klebsiella, than the compounds of this European Patent Application. The compounds of general formulae I and I' may be prepared, for example, according to the following processes which processes constitute further features of the present invention: 1) By reaction of a compound of formula V,

(wherein A is as hereinbefore defined and Y represent a carboxy or protected carboxy group), with a compound offormula VI,

(wherein R is as hereinbefore defined and B represents a group of formula -NCO or a reactive derivative of a group of formula -NHCOOH, such as, for example, a group of formula

the group NHCOCI being particularly preferred) followed where required by deprotection of the carboxy group. It is also possible to use mixtures of compounds of general formula VI having different groups B, e.g. the groups -NCO and -NHCOCI. The compounds of general formula V may, if desired be used in the form of their inorganic or organic salts, e.g. as the triethylammonium salt or sodium salt. In this case the reaction is conveniently effected in the presence of a mixture of water and a water-miscible organic solvent, such as, for example, a keytone, e.g. acetone; a cyclic ether, e.g. tetrahydrofuran or dioxan; a nitrile, e.g. acetonitrile; a formamide, e.g. dimethylformamide; dimethylsulphonoxide or an alcohol, e.g. isopropanol, or in hexametapol. The pH of the reaction mixture is preferably kept within a pH range of from 2.0 to 9.0, most preferably from pH 6.5 to 8.0, by the addition of bases or by using buffer solutions.It is also possible to perform the reaction in the presence of an anhydrous organic solvent, e.g. a halogenated hydrocarbon such as e.g. chloroform or methylene chloride, with the addition of a base, preferably triethylamine, diethylamine or N-ethylpiperidine. Moreover, the reaction may also be carried out in a mixture of water and a water-immiscible solvent, such as for example an ether, e.g. diethyl ether; a halogenated hydrocarbon, e.g. chloroform or methylene chloride; carbon disulphide; a ketone, e.g. isobutyl methyf ketone; an ester, e.g. ethyl acetate; or an aromatic solvent, e.g. benzene. Such reactions are preferably carried out with vigorous stirring and preferably keeping the pH at from 2.0 to 9.0, most preferably from 6.5 to 8.0, by the addition of a base or using buffer solutions. The reaction may also be carried out in water in the presence of an organic or inorganic base or with the addition of buffers. The compounds of general formula V may alternatively be used, if desired, in the form of an ester, e.g. a silyl ester. If a silyl ester (e.g. the mono- or di-trimethylsilyl ester) is reacted with the compound of formula VI, it is generally preferred to work in anhydrous solvents free from hydroxyl groups, e.g. in halogenated hydrocarbons, for example, methylene chloride or chloroform; benzene, tetrahydrofuran, acetone or dimethylformamide. The addition of bases is not essential but may be advantageous in certain cases to improve the yield and purity of the products. Suitable, bases include, for example, tertiary aliphatic and aromatic amines such as e.g. pyridine and triethylamine and sterically hindered secondary amines, i.e. those difficult to acylate on account of steric hindrance, such as e.g. dicyclohexylamine. Other esters which may be used as the compound of formula V are, for example, those which are known in the art for the preparationof semi-synthetic pencillins. Typical examples are the trityl, pnitrobenzyl and phenacyl esters. After the reaction, these ester derivatives may, where necessary, be converted to the desired pencillin according to the invention, using known methods. The amount of base preferably used is generally dictated by the desirability of maintaining a particular pH. Where measurement and adjustment of the pH is not carried out or is not possible or practical owing to a lack of sufficient water in the solvent, then preferably 1.0 to 2.0 mol equivalents of base are added when non-silyl compounds of general formula IV are used. When a silyl ester of formula IV is used, preferably up to one mol equivalent of base is used. As bases, it is possible to use any of the organic and inorganic bases conventionally used in organic chemistry, such as e.g. alkali and alkaline earth metal hydroxides, alkaline earth metal oxides, alkali and alkaline earth metal carbonates and hydrogen carbonates, ammonia, primary, secondary and tertiary aliphatic and aromatic amines and heterocyclic bases. Such bases include, for example sodium, potassium and calcium hydroxide; calcium oxide; sodium and potassium carbonate; sodium and potassium hydrogen carbonate; ethylamine, methylethylamine, triethylamine, hydroxyethylamine, aniline, pyridine and piperidine. However, when silyl starting materials are used, the above restrictions regarding the types of bases should be observed. As buffer systems it is possible to use any conventional buffer mixture, e.g. phosphate buffer, citrate buffer and tris(hydroxymethyl)amino-methane buffer. The reaction temperatures may be varied with a fairly wide range. Generally, it is preferred to work at from -20 to +50[deg]C, most preferably at from 0 to +20[deg]C. The reactants of general formulae IV and V are, in general, conveniently reacted in substantially equimolar amounts. In certain cases, however, it may be advantageous to use one of the reactants in excess so as to facilitate purification of the end product or increase the yield. 2) By reaction of a compound of formula VII,

(wherein A and R are as hereinbefore defined) or a reactive derivative thereof, with a compound of formula VIII,

(wherein Y is as hereinbefore defined) followed, where required by deprotection of the carboxy group, e.g. by hydrolysis or catalytic hydrogenation. The reaction may be effected according to methods conventional in /3-lactam chemistry. Examples of reactive derivative of formula VII include, for example, acid anhydrides such as e.g. those derived from esters of chloroformic acid, e.g. ethyl or isobutyl chloroformate; reactive esters such as e.g. the p-nitrophenyl ester and the N-hydroxysuccinimide ester; and reactive amides such as e.g. the N-carbonylimidazole; as well as acid halides e.g. the acid chloride; and acid azides. The compound of formula VIII is preferably used in a form in which the carboxy group is protected. Thus preferred compounds of general formula VIII include, for example, the trimethylsilyl ester, trityl ester, p-nitrobenzyl ester, phenacyl ester and the O,N-bis-trimethylsilyl ester. These ester compounds are preferably reacted in the presence of an aprotic solvent such as e.g. methylene chloride or tetrahydrofuran. Alternatively, the compound of formula VIII may be used in the form of a salt, e.g. the triethylammonium salt. In such cases the reaction is preferably carried out in the presence of methylene chloride, a protic solvent, an aqueous medium or an aqueous-organic solvent, such as e.g. aqueous tetrahydrofuran. The reaction is generally effected in the presence of a solvent, preferably at temperatures of from -40[deg]C to +40[deg]C and optionally in the presence of a base. If, for example, an anhydride of the ureidocarboxylic acid of formula VII, e.g. the anhydride with ethyl chloroformate is reacted with a compound of formula VIII where Y represents a protected carboxy group, the reaction is conveniently carried out with cooling, for example at -10[deg] to +10[deg]C in the presence of a tertiary amine, such as e.g. triethylamine or N,N-dimethylaniline and of a solvent such as e.g. acetone, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane, hexametapol or a mixture thereof.If, for example, an N-hydroxysuccinimide ester of the ureidocarboxylic acid of formula VII is reacted with the 6aminopenicillanic acid of formula VIII (Y=COOH), the reaction is preferably carried out at 0 to 20[deg]C in the presence of a base, e.g. triethylamine, and of a solvent such as e.g. dimethylformamide, dichloromethane, dioxan or a mixture thereof. The reaction of a ureidocarboxylic acid of formula VII itself or a salt thereof with 6-aminopenicillanic acid or a salt thereof is advantageously carried out in the presence of a condensing agent, e.g. in the presence of N,N'-dicyclohexylcarbodiimide. In the above described processes (1) and (2), where a compound of formula V or VIII is used where Y represents a protected carboxy group a product may be obtained, which may still depending on the reaction conditions employed, contain the carboxy protecting group. Such protecting groups may, however, be easily removed according to methods well known in the art. Thus, for example, where the protected carboxy group is present in the form of the silyl ester, this group may subsequently be converted by hydrolysis to the desired carboxy group. In other cases, e.g. a p-nitrobenzyl ester group, if present, may be removed by hydrogenolysis to give the desired carboxy group. Further processing of the reaction mixture obtained by both processes may be carried out according to methods conventionally used in /3-lactam chemistry, e.g. isolation and purification of the end products, liberation of the free acids from their salts and the conversion of the free acids into salts by means of inorganic or organic bases. For preparing the potassium and sodium salts it has proved particularly useful to precipitate these salts from an alcoholic-ethereal solution of the free acid, by adding potassium or sodium 2-ethylhexanoate. The compounds of general formula V useful as starting materials are known from the literature, see for example E. H. Flynn, Cephalosporins and Penicillins, Academic Press, New York and London (1972). The starting materials of general formula VI may be obtained, for example, by reacting a corresponding 5-aminopyrimidine of formula IX

(wherein R is defined as above) with phosgene. This reaction is preferably carried out in a solvent which does not contain hydroxyl groups, such as e.g. tetrahydrofuran, methylene chloride, chloroform, dimethoxyethane or hexametapol and at temperatures of from -40[deg] to +60[deg]C, most preferably at from . -10[deg] to +20[deg]C. It is, in general, advisable to bind the resultant hydrogen chloride with equimolar quantities of an inert organic base such as e.g. triethylamine or pyridine. Pyridine in excess may also be used as the solvent. If the aminopyrimidine of formula IX does not dissolve readily in one of the abovementioned solvents, phosgenation may also be effected in the heterogeneous phase. Moreover, the aminopyrimidines of general formula IX may be converted, by treating them with a silylating agent such as e.g. hexamethyldisilazane, trimethylchlorosilane/triethylamine or N,O-bis-trimethylsilylacetamide, into the corresponding mono- or polysilylated aminopyrimidine, depending on the number of exchangeable hydrogen atoms present, which is generally very readily soluble in the above-mentioned solvents.This aminopyridine may then be reacted with phosgene to form the corresponding compound of formula VI. Depending on the solvent, temperature and amount and nature of the base used, either mainly the corresponding isocyanate or carbaminic acid halide or a mixture of these is obtained. Depending on the reaction conditions, the compound of formula VI may also occur to some extent as a dihydro-oxazolopyrimidine of formula Via

this compound being isomeric with the isocyanate, or, in the event of previous silylation, as a mono- or polysilylated analogue, depending on the nature of the substituent R. The starting materials of general formula VI or mixtures thereof obtained by phosgenation as described above are generally readily soluble in the above-mentioned solvents and, after removal of the excess phosgene, can be reacted directly, without further purification, with the penicillin derivatives of formula V. However, it is also possible, if desired, to isolate the intermediate product of formula Via, desilylate it with a protic solvent, e.g. with methanol or water, if required, purify it on the basis of its solubility characteristics and react it in the manner described above. The preparation of 2-substituted 5-amino-4-hydroxypyrimidines of general formula IX, inasmuch as it is not already described in European Patent Application No. 79 100 468.2, is described more fully in the Examples which follow. A particularly suitable method is to react 2-chloro-4-hydroxy-5nitropyrimidine with anilines or benzylamines in aqueous solution and then to reduce the nitro group by methods known perse, or to react 5-benzoylamino-4-hydroxy-2-methylmercaptopyrimidine with the corresponding aniline or benzylamine in the melt or in a high-boiling solvent such as sulfolan: The ureidocarboxylic acid derivatives of general formula VII are easily obtained by reacting a pyrimidine derivative of formula VI with a glycine derivative of formula X

(wherein A is defined as hereinbefore). The reaction may be carried out at temperatures of from -20[deg] to +40[deg]C, preferably from 0[deg] to +20[deg]C and in a solvent. Suitable solvents include, for example, mixtures of water and water-miscible organic solvents, such as e.g. acetone, tetrahydrofuran, dioxan, acetonitrile, dimethylformamide, ethanol and dimethyl sulfoxide. It may be desirable to use a hydrogen halidebinding agent; suitable agents include, for example, trialkylamines, such as e.g. triethylamine and inorganic bases such as e.g. dilute sodium hydroxide solution. As mentioned above the compounds of general formulae I and I', as well as their salts have interesting biological properties whilst being well tolerated. Those compounds which we have tested exhibit good bacteriocidal activity against both gram-negative and gram-negative bacteria. Such compounds can therefore be used in the prophylaxis and chemotherapy of local and systemic infections in both humans and animals. Thus, these compounds are of use in the prevention and/or cure of, for example diseases of the respitatory tract, the pharyngeal cavity and the urinary tract, particularly pharyngitis, pneumonia, peritonitis, pyelonephritis, otitis, cystitis, endocarditis, bronchitis, arthritis and general systemic infections. The compounds according to the invention are extremely effective both in vitro and in vivo against harmful microorganisms, particularly gram-positive and gram-negative bacteria and microorganisms resembling bacteria, and they are distinguished particularly by a broad spectrum activity. When administered by the parenteral route, these compounds show high levels in the tissues, serum, organs and urine. These compounds may also be used as preservatives in inorganic or organic materials, particularly organic materials such as e.g. polymers, lubricants, dyes, fibres, leather, paper and wood as well as foodstuffs. The following Table I lists some typical, particularly effective penicillins according to the invention. These penicillins may be prepared according to process 1 or 2: The compounds concerned are those wherein A and R are defined as follows: TABLE 1

TABLE 1 (Continued)

TABLE 1 (Continued)

The penicillin derivatives according to the invention may be used, for example, to treat and/or prevent local and/or systemic diseases caused by the following pathogens or mixtures thereof: Micrococcaceae, such as Staphylococci; Lactobacteriaceae, such as Streptococci; Neisseriaceae, such as Neisseriae; Corynebacteriaceae, such as Coryne bacteria; 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 Brucellaceae, 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; Fusiforme bacteria, e.g. Fusobacterium fusiforme; Sphaerophorus bacteria, e.g. Sphaerophorus necrophorus; Bacillaceae, such as aerobic spore formers, e.g. Bacillus anthracis; anaerobic spore-forming Chlostridiae, 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 pathogens is purely by way of example and is in no way restrictive. The effectiveness of the penicillins according to the invention can be demonstrated by way of example by the following tests. 1. Tests in vitro The tests were performed using the series dilution method in the microtiter system. The substances were tested for bacteriostasis in a liquid medium. The bacteriostatic activity was tested at the following concentrations: > 64; 64; 32; 16; 8; 4; 2; 1; 0.5; 0.25; 0.125; 0.06; 0.03; 0.015 and 0.007 Microg/ml. A nutrient medium having the following composition was used: 10 g of peptone, 8 g of meat extract oxoid, 3 g of sodium chloride, 2 g of sec. sodium phosphate are made up to 100 ml with distilled water (pH 7.2 to 7.4). 1 % glucose was added only for the tests against Streptococci. The age of the primary cultures was about 20 hours.The bacterial suspension was adjusted using a photometer (according to "Eppendorf") (test tube diameter 14 mm, filter 546 nm) by reference to the turbidity of a ) barium sulphate comparison suspension which was produced by a barium sulphate suspension formed by the addition of 3.0 ml of 1 % barium chloride solution to 97 ml of 1 % sulphuric acid. After adjustment, Streptococcus aronson was diluted in a ratio of 1:15 and the other test pathogens were diluted further in a ratio of 1:1500 with saline solution. 16 mg of the test substance were weighed in 10 ml measuring flasks and solvent was added up to the mark. Further dilutions in the series were made with distilled water or the solvent in question. The depressions in the microtiter plates were filled with 0.2 ml of nutrient medium, 0.01 ml of the corresponding diluted substance and drop of bacterial suspension (0.01 ml) and a drop of bacterial suspension (0.01 ml) and incubated for 18 to 20 hours at 37[deg]C. A solvent check was carried out continuously at the same time. The reading was taken macroscopically, and the respective limiting concentration (= the lowest concentration still having bacteriostatic activity) was determined. The following were used as test organisms: Staphylococcus aureus SG 511, Escherichia coli ATCC 11 1 775, Pseudomonas aeruginisa Hamburgenis, Pseudomonas aeruginose Walter, Serratia marcescens ATCC 13 880, Klebsiella pneumoniae ATCC 10 031 and BC 6, Proteus mirabilis Hamburgensis BC 17; Proteus rettgeri BC 7 and Enterobacter cloacae ATCC 13 047. Table 2 which follows lists the minimum inhibitory concentrations (MIC) detemined for typical representatives of the compounds according to the invention, the compound numbers referring to the penicillins as listed in Table 1.

A number of the compounds according to the invention were tested in vivo on experimental infections in mice. E. coli ATCC 11775 and Pseudomonas aeruginosa Walter were used as the pathogenic bacteria. An intraperitoneal infection was produced with 0.2 ml of a 5% mucin suspension of the bacteria. This corresponds to about 2 x 106 E. coli bacteria and 8 x 105 Pseudomonas bacteria per mouse. Female mice of the NMRI strain were divided up into groups of 10 animals, two groups were untreated, the other groups were treated with various doses of the penicillins according to the invention, to determine the ED50 (dose at which 50% of the animals survived). For the E. coli infection, one treatment was given. For the Pseudomonas infection, three treatments were given. In both cases, the observation period was 7 days. The results of these tests with representative penicillins according to the invention are shown in Table 3.

TABLE 3 As comparison substances the known penicillins of general formula

were used wherein R = H : azlocillin = A R=SO2CH3 : mezlocillin = B and also D-alpha -[4-hydroxy-3-pyridyl)-ureido]benzylpencillin sodium (cf DE-OS 2450 668) = C and piperacillin = D Values in vivo

The acute toxicity was determined by oral and subcutaneous administration of the compounds of Table 1 in increasing doses to white laboratory mice. The LD50 is the dose which results in the death of 50% of the animals within 8 days. All the substances had an LD50 of over 4 g/kg when administered orally and an LD50 of over 3 g/kg when administered subcutaneously, i.e. no animals died at a dose of 3 g/kg, and the substances are therefore substantially non-toxic in dosages for practical use. The data given shows that the above penicillins according to the invention are useful antibiotics having a broad antibiotic spectrum, high antibacterial activity, low toxicity and high serum levels after subcutaneous and oral administration. According to a further feature of the invention there are provided pharmaceutical compositions comprising as active ingredient, at least one compound of formula I or I' as hereinbefore defined or a physiologically compatible salt theeof in association with a pharmaceutical carrier or excipient. For pharmaceutical administration the compounds of general formula I and I' and their physiologically compatible salts may be incorporated into conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for oral, rectal or parenteral (including topical) administration. Preferred forms include, for example, plain tablets, coated tablets, capsules, granulates, suppositories, solutions, suspensions, emulsions, ointments, gels, creams, powders and sprays.Conveniently the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Advantageously, the active ingredients according to the invention are administered, in human or veterinary medicine, in a dose of from 5 to 500, preferably 10 to 200 mg/kg of body weight per 24 hours, optionally in the form of several single doses. A single dose will preferably contain the active ingredient according to the invention in amounts of from 1 to 100, more particularly 5 to 60 mg/kg of body weight. However, it may be necessary to deviate from the doses states above, depending on the nature and body weight of the patient being treated, the nature and gravity of the disease, the type of preparation and the method of administration of the pharmaceutical product and also the period or interval within which the product is administered.Thus, in some case, it may be adequate to use less than the above-mentioned quantity of active substance, whereas in other cases it may be necessary to use more than the amount of active ingredient specified above. The optimum dose and method of administration of the active ingredients required in each case can readily be determined by anyone skilled in the art from his specialised knowledge. For parenteral administration it is preferred to dissolve the penicillin according to the invention in a non-toxic liquid medium for injection purposes and to inject the solution by intramuscular, intravenous or subcutaneous route. It is also possible to dissolve the penicillin compond according to the invention in a non-toxic liquid medium or in anointment base or to mix it therewith, and to apply the solution or mixture directly to the affected area. The compounds may also be used as suppositories after being mixed with, or dissolved in, a base for suppositories. Examples of non-toxic liquid medium which may be used for the preparation of injectable preparations containing the penicillin compound as active ingredient are sterilised deionised water, physiological saline solution, glucose solution for injection, Ringer's solution and amino acid solution for injection. The penicillin may also be dissolved in other injectable preparations and administered parenterally. For oral administration, the penicillin compounds according to the invention may conveniently be formulated with pharmaceutically acceptable carriers such as, for example, organic and inorganic solid and liquid excipient suitable for oral administration. If desired, these preparations may also contain auxiliary substances, stabilisers and other conventional additives. According to a further feature of the invention there is provided a method of treating a patient suffering from or susceptible to a bacterial infection which comprises administering to said patient an effective amount of a compound of formula I or I' or a physiologically compatible salt thereof. The new compounds, as mentioned above, may also be incorporated into various inorganic and organic materials e.g. foodstuffs and drinking water according to conventional methods so as to prevent and/or remove infections by gram-negative and gram-positive bacteria. Thus according to a yet further feature of the invention there is provided a method of preserving inorganic or organic material against bacterial attack which comprises treating said material with an effective amount of a compound of formula I or I' or a salt thereof. The following non-limiting Examples serve to illustrate the invention in more detail: (The Rf values given refer to the system n-butanol/water/glacial acetic acid = 60:25:15, SiO2 plate). "Ampicillin" refers to a-aminobenzylpenicillin, "amoxicillin" to a-amino-p-hydroxybenzylpenicillin and "epicillin" to alpha -amino-alpha -(1,4-cyclohexadien-1-yl)-methylpenicillin with the D=R configuration in the side chain.

EXAMPLE A I. Preparation of the starting compounds 5-Amino-4-hydroxy-2-p-methylsulfonylanilino-pyrimidine 3.2 g (0.019 mol) of 4-methylthio-nitrobenzene are dissolved in 20 ml of formic acid and at ambient temperature added to 0.05 mol of hydrogen peroxide as a 30% solution. The solution heats up. After standing for 1 hour at ambient temperature, the product is precipitated with ice water. The precipitate is suction filtered and dried in vacuo at50[deg]C. 2.9 g (76.2% of theory) of p-nitrophenylmethylsulphone are obtained. 3.42 g (0.017 mol) of p-nitrophenyl-methyl-sulphone are dissolved in 100 ml of methanol and hydrogenated in the presence of 1 g of Raney nickel at 50[deg]C and at 5 bars. The solution is filtered off from the catalyst and evaporated to dryness.The residue is dissolved in 40 ml of dioxan and a solution of 3.77 g (0.0175 mol) of 2-chloro-4-hydroxy-5-nitro-pyrimidine sodium salt x 1 H20 in 120 ml of water is added. The solution is heated over a steam bath for 3 hours. After cooling, the precipitate formed is suction filtered, washed with water and dried in vacuo at 50[deg]C. Yield: 3.1 g (58.7% of theory) of 4-hydroxy-2-p-methyl-sulfonylanilino-5-nitropyrimidine. 3.3 g (0.01063 mol) of 4-hydroxy-2-p-methylsulfonylanilino-5-nitropyrimidine are dissolved in 50 ml of water by adding 6 ml of concentrated ammonia and heating. 7.83 g (0.045 mol) of sodium dithionite are added all at once, with stirring. The mixture is then stirred at 60[deg]C for another 15 minutes. After cooling, the precipitate formed is suction filtered, washed with water and dried in vacuo at 50[deg]C. Yield: 2.4 g (80.6% of theory) of 5-amino-4-hydroxy-2-p-methylsulfonylanilino-pyrimidine. NMR spectrum (DMSO + CD30D) signals at ppm: 3.15 (s,3H), 7.2 (s,1 H), 7.8 (broad, s,4H).

EXAMPLE B 5-Amino-4-hydroxy-2-p-methylsulfinylanilino-5-nitropyrimidine are suspended in 50 ml of glacial acetic acid, added to 2.3 g (0.02 mol) of 30% hydrogen peroxide and heated over a steam bath for 10 minutes, with stirring. After cooling, the precipitate formed is suction filtered and dried in vacuo. Yield: 2.28 g (55% theory) of 4-hydroxy-2-p-methylsulfinylanilino-5-nitro-pyrimidine. 2.1 g (0.0079 mol) of 4-hydroxy-2-p-methylsulfinylanilino-5-nitropyrimidine are suspended in 60 ml of water and dissolved by addition of 7 ml of cone. ammonia and heating. 8 g of sodium dithionite are added all at once and the solution is heated for 20 minutes over a steam bath. After cooling, the solution is adjusted to pH 7 with glacial acetic acid and left to stand in a refrigerator for several hours. After suction filtering, the crude product is purified by chromatography over a silica gel column (eluant: chloroform/methanol 5:1). Yield: 0.8 g (38.2% of theory). NMR spectrum (DMSO + CD30D) signals at ppm: 2.75 (s,3H), 7.15 (s,1 H), 7.7 (q,4H). The pyrimidines listed in the following Table were synthesised analogously, starting from the correspondingly substituted aniline and 4-hydroxy-2-p-methylthioanilino-5-nitro-pyrimidine or 2chloro-4-hydroxy-5-nitropyrimidine with subsequent reduction. Pyrimidines of general formula:

EXAMPLE C

Pyrimidines of general formula

Pyrimidines of general formula

2.95 g (0.01 mol) of 5-amino-2-p-methylaminosulfonylanilino-4-hydroxy-pyrimidine are refluxed for 30 minutes in 100 ml of dry tetrahydrofuran with 6 g of trimethylsilyldiethylamine. The mixture 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, whilst cooling with ice, to 1.05 g of phosgene, dissolved in 50 ml of tetrahydrofuran. The mixture is stirred for a further 5 minutes at ambient temperature and evaporated down to about half the volume, in vacuo.This solution is added dropwise, whilst cooling with ice, to 1.57 g (0.01 mol) of D,L-thienylglycine dissolved with 1 N sodium hydroxide solution in a mixture of 50 ml of tetrahydrofuran and 20 ml of water. At the end of the addition, the pH value is adjusted to 8.0. The mixture is stirred at ambient temperature for one hour, then the tetrahydrofuran is eliminated in vacuo, a little water is added and the mixture is extracted twice with ethyl acetate, pH 7.0. The aqueous phase is then adjusted to pH 2.7 with 2 N hydrochloric acid. The precipitated product is suction filtered 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,1 H), 7.05 (m,2H), 7.40 (m,1 H), 7.80 (q,4H), 8.35 (s,1 H). The following ureidocarboxylic acids were synthesised analogously: a) Ureidocarboxylic acids of general formula:

b) Ureidocarboxylic acids of general formula

c) Ureidocarboxylic acids of general formula

II. Preparation of the end products EXAMPLE 1

hydroxybenzylpenicillin 1.47 g (0.005 mol) of 5-amino-4-hydroxy-2-p-methylaminosulfonylanilino-pyrimidine are suspended in 50 ml of dry tetrahydrofuran and refluxed with 4 g of trimethylsilyldiethylamine until completely dissolved (10 to 30 minutes). The solution is evaporated to dryness in vacuo, taken up again in 50 ml of dry tetrahydrofuran and added dropwise to a solution of 530 mg of phosgene in 35 ml of dry i tetrahydrofuran, whilst cooling with ice.The mixture is stirred for a further 10 minutes at ambient temperature and then evaporated down to half the volume in vacuo. 2.1 g (0.005 mol) of amoxicillin are suspended in a solvent mixture of 40 ml of tetrahydrofuran and 10 ml of water. Whilst cooling with ice, triethylamine is added until a solution is formed. The solution prepared above is added dropwise to this solution, whilst the pH is maintained at about 7.0 by ; adding triethylamine. The mixture is stirred for another hour in an ice bath, allowed to come back to ambient temprature, then 20 ml of water are added and the tetrahydrofuran is eliminated in vacuo. The aqueous phase is extracted once with ethyl acetate at pH 7.0 and then adjusted to pH 2.8 with 1 N hydrochloric acid, whilst cooling with ice. The penicillin is precipitated and dried in vacuo. By addition of the calculated quantity of sodium ethylhexanoate in methanol, the sodium salt is prepared and precipitated with ether. Yield: 2.16 g (62%); IR spectrum: 1765, 1650, 1610 cm-'; NMR spectrum (DMSO + CD30D) signals at ppm: 1.55 (d,6H), 2.55 (s,3H), 4.05 (s,1 H), 5.45 (d + s, 3H), 6.75 (d,2H), 7.30 (d,2H), 7.85 (q,4H), 8.35 (s,1 H). The penicillins of the following formulae were synthesised by this method:

Moreover, penicillins of formula

were prepared analogously:

EXAMPLE 50

A solution of 2.3 g (5 mmol) of D,L-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)ureido]-thienylacetic acid in 50 ml of dimethylformamide and 25 ml of methylene chloride is mixed with 0.52 g (5.1 mmol) of N-methylmorpholine and cooled to -20[deg] to 25[deg]C. 0.54 g (5 mmol) of ethyl chloroformate dissolved in 20 ml of methylene chloride is added thereto and the mixture is stirred for 45 minutes at -20[deg]. (Solution A). 3.1 g (30 mmol) of triethylamine are added dropwise to a suspension of 1.1 g (5 mmol) of 6aminopenicillanic acid in 50 ml of methylene chloride, then stirred for 1-2 hours at ambient temperature until a solution is formed and subsequently cooled to -20[deg]C (Solution B). Solution B is added to solution A, whilst the temperature is maintained at -20[deg]C, and the reaction mixture is reacted for 45 minutes at -20[deg] and for 2 hours at ambient temperature. 150 ml of water are then added, the pH of the aqueous phase is adjusted to 7.2, the organic layer is removed and the aqueous phase is extracted 3 times with ethyl acetate. The ethyl acetate extracts are discarded. Ethyl acetate is added to the aqueous phase and the pH is adjusted to 3.0 by adding 2 N hydrochloric acid. The organic layer is separated, dried with sodium sulphate and concentrated by evaporation. The penicillin obtained is dissolved in methanol and the sodium salt is precipitated out by the addition of an equimolar amount of sodium ethylhexanoate. Yield: 2.9 g (84% of theory), IR spectrum: 1760, 1655, 1600 cm-1, NMR spectrum (DMSO + CD30D) signals at ppm: 1.55 (d,6H), 4.0 (s,1 H), 5.45 (m,3H), 7.1 (m,2H), 7.45 (m,1 H), 7.85 (q,4H), 8.35 (s,1 H).

EXAMPLE I The following penicillins were synthesised using the method described in Example 50: a) of the formula

b) of the formula

c) of the formula

Tablets containing sodium D-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido]benzylpenicillin A mixture consisting of 2 kg of active substance, 5 kg lactose, 1.8 kg potato starch, 0.1 kg of magnesium stearate and 0.1 kg of talc is compressed in the usual way to form tablets, each containing 200 mg of active substance.

EXAMPLE II Coated tablets containing sodium D-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido]benzylpenicillin Compressed tablets are produced as in Example I and are then covered in the usual way with a coating consisting of sugar, potato starch, talc and gum tragacanth.

EXAMPLE III

benzylpenicillin 5 kg of active substance is packaged in hard gelatine capsules in the usual way, each capsule containing 500 mg of the active substance.

EXAMPLE IV Dry ampoules containing sodium D-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido]benzylpenicillin Under aseptic conditions, 251 g of active substance were dissolved in 200 ml of distilled water for injection. The solution was filtered through a Millipore filter (pore size 0.22 mm, product of the Millipore Corporation, Bedford, USA). 2.0 ml amounts of the solution were poured into 1000 vials (capacity 10 ml) and lyophilisation was carried out. The vials were then sealed with a rubber stopper and an aluminium cover. In this way, vials (No. A) were obtained, each containing 250 mg of active substance. A physiological saline solution for injection was poured into ampoules in amounts of 2.0 ml and the ampoules were sealed. In this way, ampoules (No. B) were obtained. The physiological saline solution in the ampoules (No. B) was poured into the vials (No. A) this producing an injectable preparation suitable for intravenous administration. Distilled water for injection was poured into the vials (No. A) in amounts of 20 ml and the solution was dissolved in a 5% solution of glucose for injection (250 ml). In this way, solutions for continuous infusion were prepared. Tablets, coated tablets, capsules and ampoules containing one or more of the other active substances of formula I or the physiologically compatible salts of these compounds can be obtained analogously.

Claims (1)

1. Compounds of general formula I,

and their tautomers of general formula I'

wherein either a) A represents a phenyl group and R represents a group of formula II,

[in which n is 0 or 1 and R, represents the group -NH-CO-NH2; -NO2; -CO-NH2; -CO-NHCH3; -CO-N(CH3)2; -0-CO-CH3; -SO3R4; -SO-R4; SO2NH2; -SO2-NH-R4 or -SO2-N(R4)2 (where R4 represents an alkyl group with 1 to 4 carbon atoms) or, when n is 1, alternatively a hydrogen or fluorine atom or a hydroxy, methyl or methoxy group]; or R represents a group of formula III

(in which one of R2 and R3 represents a hydroxy group and the other represents a group of formula -SO2-NH2; -CO-NH2; or CO-NH-CH3 or both group R2 and R3 each represent the group -CONH2); or or b) A represents a hydroxyphenyl group and R represents a group of formula II as defined above [in which n is 0 or 1 and R, represents the group -NH-CO-NH2; -CO-NH-CH3; -CO-N(CH3)2; -0-CO-CH3; -SO-R5; -SO2-R5; S02-NH-R4; -SO2-N(R4)2 or -SO2-NH2 (where R4 is as defined above and R5 represents an alkyl group with 2 to 4 carbon atoms) or, when n is 1, alternatively a fluorine atom, a hydroxy group, a nitro group, a group H2NCO-, a group -SO-CH3, -S02-CH3 or p-HZN-SO2- , or a methyl or methoxy group, with the proviso that, when n is 0 and R, represent the group -SO2NH2, R, is in the meta position] or R represents a group of formula III (in which one of the groups R2 and R3 represents a hydroxy . group and the other represents a group of formula -SO2-NH2; -CO-NH2; -CO-NH-CH3 or both groups R2 and R3 each represent a group -CONH2); or c) A represents a 2-thienyl, cyclohexa-1,4-dien-1 -yl, 3,4-dihydroxyphenyl or 3-chloro-4hydroxyphenyl group and R represents a group of formula II as defined above [in which n is 0 or 1 and R, represents a hydrogen or fluorine atom, a methyl, methoxy, hydroxy or acetoxy group or a group of formula H2N-CO-NH-; H2N-CO-; CH3-NH-CO-; (CH3)2N-CO;-SO-R4;-SO2- R4;-SO2-NH2; -SO2-NH-R4 or-SO2-N(R4)2 (where R4 is as defined above) with the proviso that R, may only represent a hydrogen atom when A represents a 2-thienyl, 3,4-dihydroxyphenyl or 3-chloro-4hydroxyphenyl group and R, may only represent a hydroxy oracetoxy group when A represents a 2thienyl, cyclohexa-1,4-dien-1-yl or 3-chloro-4-hydroxyphenyl group] or R represents a group of formula III as defined above (in which R2 represents a hydroxy group and R3 represents a hydroxy group or a group -CONH2, -CO-NHCH3 or SO2NH2 or both groups R2 and R3 may each represent the group -CONH2; and the salts thereof with inorganic or organic bases.

2. Compounds as claimed in claim 1 wherein R represents a group of the formula:

3. Compounds as claimed in claim 1 wherein either: a) R represents a group

and A represents a phenyl, 2-thienyl, 3-chloro-4-hydroxyphenyl, 3,4-dihydroxyphenyl or 1,4cyclohexadien-I-yl group, or

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

and A represents a phenyl or p-hydroxyphenyl group. 0 4. Sodium D-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido]-benzylpenicillin.

benzylpenicillin. 5 7. Sodium D, L-a-[3-(2-p-aminosulfonylanilino-4-hydroxy-5-pyrimidinyl)-ureido]-m-chloro-phydroxy-benzylpenicillin.

cyclohexadien-1-yl-methylpenicillin. b) R represents a group

benzylpenicillin.

10. Sodium D-a-[3-(4-hydroxy-2-p-methylaminosulfonylanilino-5-pyrimidinyl)-ureido]benzylpenicillin. 11. Sodium D,L-a-[3-(4-hydroxy-2-p-methylaminosulfonylanilino-5-pyrimidinyl)-ureido]-mchloro-p-hydroxy-benzylpenicillin.

12. Sodium D-a-[3-(4-hydroxy-2-p-methylsulfinylanilino-5-pyrimidinyl)-ureido]-benzylpenicillin.

hydroxy-benzylpenicillin.

14. Sodium D-a-[3-(2-(p-aminosulfonyl-m-hydroxyanilino)-4-hydroxy-5-pyrimidinyl)-ureido]-phydroxy-benzylpenicillin.

benzylpenicillin.

16. Compounds as claimed in claim 1 having the D=R configuration.

17. Physiologically compatible salts with bases of the compounds of gneral formulae I and I' as defined in claim 1.

18. Compounds as claimed in claim 1, other than those claimed in any one of claims 4 to 15, as herein specifically disclosed in any one of Examples 1 to 67. 19. A process for the preparation of compounds of general formula I and I' as defined in claim 1 which comprises reacting a compound of formula V,

(wherein A is as defined in claim 1 and Y represents a carboxy or protected carboxy group) with a compound of formula VI,

(wherein R is as defined in claim 1 and B represents a group of formula -NCO or a reactive derivative of a group of formula -NHCOOH), followed, where required, by deprotection of the carboxy group.

20. A process as claimed in claim 19 wherein, in the compound of formula VI, B represents a group of formula NHCOCl,-NHCOBr or

21. A process as claimed in claim 19 or claim 20 wherein the compound of formula V is reacted with a mixture of compounds of general formula VI having different groups B. 22. A process as claimed in any one of claims 19 to 21 wherein the reaction is effected at temperatures of from 0 to +20[deg]C.

23. A process as claimed in any one of claims 19 to 22 wherein, in the compound of formula V, Y represents a salified carboxy group.

24. A process as claimed in claim 23 wherein the reaction is effected in the presence of a mixture of water and a water-miscible organic solvent or of water and a water-immiscible organic solvent.

25. A process as claimed in claim 23 wherein the reaction is effected in the presence of an anhydrous organic solvent and of a base.

26. A process as claimed in claim 23 wherein the reaction is effected in the presence of water and of either a base or a buffer agent.

27. A process as claimed in any one of claims 23 to 26 wherein the reaction is effected at a pH of from 6.5 to 8.0. 28. A process as claimed in any one of claims 19 to 22 wherein, in the compound of formula V, Y represents an esterified carboxy group.

29. A process as claimed in claim 28 wherein the reaction is effected in the presence of a base.

30. A process as claimed in claim 25 or claim 26 wherein, in the compound of formula V, Y represents a silylated carboxy group.

31. A process as claimed in claim 30 wherein the reaction is effected in the presence of a halogenated hydrocarbon, benzene, tetrahydrofuran, acetone or dimethylformamide as solvent.

32. A process as claimed in claim 30 or claim 31 wherein the reaction is effected in the presence of a tertiary aliphatic, aromatic, or sterically hindered secondary amine as a base. 33. A process as claimed in claim 28 or claim 29 wherein, in the compound of formula V, Y represents a carboxy group esterified with a trityl, p-nitrobenzyl or phenacyl group.

34. A process as claimed in claim 33 wherein the reaction is effected in the presence of an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkaline earth metal oxide, an alkali metal or alkaline earth metal carbonate or bicarbonate, ammonia, a primary, secondary or tertiary, aliphatic or aromatic amine or a heterocyclic base. 35. A process for the preparation of compounds of general formula I and I' as defined in claim 1 which comprises reacting a compound of formula VII,

(wherein A and R are as defined in claim 1) or a reactive derivative thereof with a compound of formula VIII,

(wherein Y is as defined in claim 19) followed, where required by deprotection of the carboxy group.

36. A process as claimed in claim 35 wherein an acid anhydride, reactive ester, reactive amide, acid halide or acid azide of the compound of formula VII is reacted with the compound of formula VIII.

37. A process as claimed in claim 35 or claim 36 wherein, in the compound of formula VIII, Y represents a carboxy group esterified with a trimethylsilyl trityl, p-nitrobenzyl, phenacyl, or 0,N-bistrimethylsilyl group. 38. A process as claimed in claim 37 wherein the reaction is effected in the presence of an aprotic solvent.

39. A process as claimed in claim 35 or claim 36 wherein, in the compound of formula VIII, Y represents a salified carboxy group.

40. A process as claimed in claim 39 wherein the reaction is effected in the presence of methylene chloride, a protic solvent, an aqueous medium or an aqueous organic solvent.

41. A process as claimed in any one of claims 35 to 40 wherein the reaction is effected at temperatures of from -40 to +40[deg]C.

42. A process as claimed in any one of claims 35 to 41 wherein the reaction is effected in the presence of a base.

43. A process for the preparation of salts of compounds of general formula I or I' as defined in claim 1 which comprises reacting a compound of formula I or I' as defined in claim 1 with a base. 44. A process for the preparation of compounds as claimed in claim 1 substantially as herein described.

45. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 67.

46. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 19 to 45.

47. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula I or I' as defined in claim 1 or a physiologically compatible salt thereof in association with a carrier or excipient.

48. Compositions as claimed in claim 48 in a form suitable for oral, or rectal or parenteral administration.

49. Compositions as claimed in claim 47 or claim 48 in the form of plain tablets, coated tablets, capsules, granulates, suppositories, solutions, suspensions, emulsions, ointments, gels, creams, powders and sprays. 50. Compositions as claimed in any one of claims 47 to 49 in the form of dosage units.

51. Pharmaceutical compositions as claimed in claim 48 substantially as herein described.

52. Pharmaceutical compositions substantially as herein described in any one of Example I to IV.

53. Inorganic and organic materials treated with a compound as claimed in claim 1.

54. A foodstuff comprising a compound of formula I or I' as defined in claim 1 or a physiologically compatible salt thereof in association with a nutrient material.

55. Compounds as claimed in claim 1 for use as bacteriocides.

56. A method of preserving an inorganic or organic material against bacterial attack which comprises treating said material with an effective amount of a compound as claimed in claim 1. 57. A method as claimed in claim 56 wherein the material is a polymer, a lubricant, a dye, a fibre, leather, paper, wood or a foodstuff.

58. A method of treating patients suffering from or susceptible to a bacterial infection which comprises administering to said patient an effective amount of a compound of formula I or I' as defined in claim 1 or a physiologically compatible salt thereof.

59. A method as claimed in claim 58 which comprises administering to said patient from 1 to 100 mg/kg of body weight of the compound of formula I or I' or physiologically compatible salt thereof in a single dose.

60. A method as craimed in claim 59 which comprises administering to said patient from 5 to 60 mg/kg of body weight of the compound of formula I or I' or physiologically compatible salt thereof in a single dose. 61. A method as claimed in any one of claims 58 to 60 which comprises administering from 5 to 500 mg/kg body weight of the compound of formula I or I' or physiologically compatible salt thereof daily.

62. A method as claimed in claim 61 which comprises administering from 10 to 200 mg/kg body weight of the compound of formula I or I' or physiologically compatible salt thereof daily.

63. Each and every novel method, process, compound and composition herein disclosed.