IL43708A - Penicillins their production and pharmaceutical compositions containing them - Google Patents

Abstract

1426199 Penicillins BAYER AG 30 Nov 1973 [1 Dec 1972 4 April 1973] 55668/73 Addition to 1301962 Heading C2C The invention comprises the compounds of formula and their salts, wherein (i) R is Me and B is either 1,4-cyclohexadien-1-yl or p-hydroxyphenyl, or (ii) R is H and B is 1,4-cyclohexadien-1-yl. In examples, these compounds are prepared by reacting the corresponding NH 2 -terminated penicillin with 2-oxo-imidazolidin-1-carbonyl chloride or its N-methyl derivative, and are converted to the Na salts. Pharmaceutical and veterinary compositions having antibacterial and growth promoting activity comprise compounds of the above formula, and may be administered orally, parenterally, rectally or locally. [GB1426199A]

Description

The present invention relates to certain new penicillin to several processes for their and to pharmaceutical compositions useful in human and veterinary The invention relates especially to the use of these compounds as therapeutic agents for mammals and as feedstuff additives and as agents in and more especially to their oral and parenteral use as above all in the case of infection by bacteria from the bacterial families Enterobacteriaceae and The present invention is a modification of the invention main claimed in Patent Specification The main invention consists in new penicillins of the formula in which formulae 2 3 and 4 denotes an alkyl group with up to 10 carbon atoms or a alkoxy alkyl an alkoxy or alkenyloxy group with up to 8 carbon or cycloalkoxy group with up to 7 carbon atoms or an aryloxy group or a group of the general formula which may be the same or are each a fluorine or ohlorine or a lower or lower alkylthio lower denotes an alky1 or alkenyl group or an aralkyl group with up to 8 carbon Z denotes a divalent group of the general formula in which a denotee the integer 3 and the arrow in the divalent group Z means that the linkage of the two free valencies of but is orientated as indicated by the is a group of the general in and may or different and are each a hydrogen or halogen atom or a lower love alkoxy or a lower lthio with the proviso that at least one and must be different from hydrogenJ a carbon atom constituting a chirallty which can be in either of the two possible and and the salts of these as well as the mixture of the possible The present invention consists in new penicillin compounds of a similar structure which are particularly defined The new compounds are acids in which the hydrogen atom on the nitrogen atom of the acylureido group which is in the is replaced by an organic group and the of the acetamido group carries a hydroxyphenyl or cyclohexadienyl It has already disclosed that certain other acids are obtainable synthetically and can be used as for penicillanic acids are described in Netherlands Patent Applications and and Patents and but all acids described and claimed in these patents have a hydrogen atom in the acylureido group on the nitrogen atom which is in the absence of a different substituent at this position of the acylureido group follows necessarily from the different method of synthesis of these acids in which the hydrogen atom of the nitrogen atom present in the of the acylureido group is replaced by an organic radical are described in German Offenlegungsschriften Israel Patent Specification and and in Belgian Patent Specification but the penicillins described and claimed there do not contain any hydroxyphenyl or cyclohexadienyl radical in the relative to the acetamido This invention now provides new compounds which are penicillins of the following general formula and their in II A is a or C Y in which X is an alkyl radical with up to 10 carbon an alkenyloxy group with up to 10 carbon lower alkylamino or alkylamino group or a phenyl group optionally substituted with and lower alkyl or a group Y is an alkyl group with up to 4 carbon Z is a divalent group of one of the following general in which G is a hydrogen atom or an alkyl radical with up to 3 carbon E is an oxygen or sulphur B is a hydroxyphenyl or cyclohexadienyl group indicates a centre of The arrow indicates that when Z is one of the asymmetric groups it can only be oriented in the direction shown by the The chirality centre can be in the two possible and The invention covers the single diastereomers and corresponding to the as well as mixtures of the Throughout this specification the expression of the includes the penicillins of general formula I and their Of the compounds of the invention that are those that are and pharmaceutically acceptable are The ahovementioned pharmaceutically tolerated salts include salts of the acid carboxyl group as aluminium and ammonium salts and substituted ammonium salts with amines as and dibenz lamine and deh droabiet lamine and other amines which have been used to form salts of The term in the present an alkyl group with up to 6 carbon In the context of other as in alk the term only relates to the alkyl part of the group in the compounds according to the invention show a substantially higher especially against bacteria from the families of the Enterobacteriaceae and Pseudomonadaceae for the known coramerically available penicillins Amnicillin and The compounds according to the invention thus represent an enrichment of The invention further provides a process for the duction of compounds according to the in a of the general is reacted with a compound of the general VI preferably in a solvent at to C in the presence of a in which general formulae II VI and VII E Y and 2 are as defined above and W is a halogen an azide group or a group of one of the following general formulae 0 a compound of the general formula is reacted with a compound of the general formula VI or VII given in preferably in a solvent at to in the presence of a base and the fragment is hydrolytically split off as the carboxyl compound in which general formulae VI and Y and Z are as defined in a compound of the general formula in which B is as ned above in a group of the general preferably in a free solvent in the absence of water and in the presence of a tertiary amine or a sterically hindered secondary amine at to with a compound of the general formula VI or to produce a product that is either the desired compound of the or B is a trialkylsilyl an intermediate which is then hydrolysed to remove the trialkylsilyl group or groups and produce the desired compound of the invention in which B is one of the phenyl radicals mentioned in which general formulae VI and and A are as defined above The above variations and of the process of the invention will be referred to throughout the rest of this specification as Process Variants and The starting compound of general formula III used in Process Variant can be regarded as a condensation product of the compound of general II used in Process Variant with the compound This carbon l compound is subsequently eliminated in Process Variant hydrolytic In the compounds of the B is preferably hydroxyphenyl or cyclohexadienyl The chirality centre is preferably in the configuration to The new free penicillanic acids of general formula I and their salts can be interconverted in any suitable methods for such interconversion are known in the In all three Process a compound of general formula VI is used when a product i which A I Y is and a compound of general formula VII is used when a product in which E II A V If and are used as starting the course of the reaction Process Variant may be illustrated by the following Le A 14 10 The compounds of the general formula II and some compounds of the general formula III which can he used as starting compounds in the process according to the invention are already known and are described in and Belgian Patent Specification Only some of the compounds of the general formula III used as starting compounds are if not described in the they can he produced the condensation of the corresponding compounds of the general formula II with carbonyl compounds of the general formula in which G is as defined with elimination of The compounds of the general formulae IV and sed starting compounds can be produced by reaction of the corresponding compounds of the general formula II with silylating agents such as Ichlorosilane or hexamethyl disilazane in the presence of agents such as triethylamine All crystalline forms and salts of the compounds of the general formulae II and III are suitable for use as starting materials for the present The con igurat on of the asymmetrical centres of the acid nucleus in the compounds of the general formulae IV and V is identical with that of the corresponding asymmetrical centres of penicillanic which has been for from by fermentative The starting compounds of the general VI and VII in which W is halogen can be produced according to processes described in German Offenlegungsschrift in German Patent Specification in Patent Specifications and in Japanese Application in German Offenlegungsschri ten Israel Patent Specification in Belgian Patent Specification and in The production of starting compounds of the general formulae and VII is furthermore described in the Possible diluents are the substances mentioned in the subsequent In Process Variants and the reactions can be carried for in water or in mixtures of water with organic solvents wich are miscible with such as tetrahydrofurane dimethyIformamide dimethylsulphoxide and The pH of the reacetion mixture in Process Variants and is for between and by adding bases or using buffer The reaction can however also be carried out in a different for example between and or at pH to It is also possible to carry out the reaction in immiscible for example chloroform or methylene preferably with the addition of diethylamine or The reaction can also be carried out in a mixture of water and a solvent as methylene carbon disulphide isobutyl methyl ethyl acetate or in which case it is advisable to stir the mixture vigorously and to maintain the pH value between and for and by adding bases or using buffer In Process Variant it is in most cases necessary to carry out the reaction in a solvent which is anhydrous and free of hydroxyl for example in methylene tetrahydrofurane acetone or The addition of bases is not necessary in that case but can in some cases improve the yield and purity of the the converse effect can also The optionally added bases are preferably either tertiary amines as pyridine or or secondary amines which are difficult to acylate owing to steric hindrance as The number of bases that can be used is therefore very The amount of base used in all Process Variants can be for by the desired maintenance of a tain Where a pH measurement and adjustment is not carried out or is not possible or meaningful because adequate amounts of water are not present in the 2 equivalents of base are preferably added in Process Variants and and either no base at 1 mol equivalent of is added in Process Variant The reaction temperatures in all Process Variants can he varied over a substantial In all the reaction is preferably carried out between and more preferably between 0 and As in the case of most chemical higher or lower temperatures than those indicated in the following examples can be if the temperatures substantially exceed the values indicated in the will increasingly which reduce the yield or have an adverse influence on the purity of the On the other excessively low reaction temperatures reduce the reaction velocity so greatly that the yield can be The reaction can be carried out under normal pressure but also under reduced or elevated In normal pressure is In carrying out the process according to the the reactants are in general reacted with one another in equimolecular it can be advisable to use one of the two reactants in excess in order to facilitate the purification of the desired penicillin or its paration in a pure and to increase the For the reactants of the general formulae II or III in Process Variants and respectively can be employed in an excess of to mol and less tion of the reactants of the general formulae VI or VII in the aqueous solvent mixture can thereby be The excess of the reactants of the general formulae II or III can easily be removed during working up of the reaction because of their good solubility in aqueous mineral On the other hand it is also with to employ the reactants of the general formulae VI or VII in an excess for results in the for of the general formulae II or utilised and compensates for the decomposition of the reactants of the general formulae VI or VII which takes place as a in aqueous Since the compounds of the general formulae VI or VII added in excess rapidly in into neutral or which can easily be the purity of the penicillin compound produced is hardly impaired The working up of the reaction batches to isolate the compound according to the invention can be carried out in the manner generally known for In Process Variant the fragment C G is hydrolytically split off from the starting compound of general formula III in the form of the carbonyl This hydrolytic splitting takes place immediately after the reaction of the compound of the general formula III with the compound of the general formula VI or if water is ent in the reaction or can be effected if the main reaction is carried out under anhydrous by working up the products in the presence of In Process Variant of starting compounds of the general ormulae IV or the hydrolytic of the trialkkylsilyl radicals is most conveniently effected the reaction products under aqueous The following and their pharmaceutically acceptable may be mentioned as preferred new pounds according to the Example penicillin Example x benzylpenicillin Example hydroxybenzylpenicillin Example penicillin Example Example 1 o hydroxybenzylpenicillin Example A 14 18 Exani le metnylpenicillin Example Example Example reido cyclo Example lpenicillin Example lpenicillin Example Le A 14 21 Example thy laminocartony hylpenicillin Example and As the compounds according to the invention are This is shown the following experiment which was carried out with the penicillin from Example 1 6as the sodium The penicillin from Example 1 was diluted with Hinton nutrient with addition of of to a content of The nutrient solution in each case 5 5 contained 1 x 10 to 2 x 10 bacteria per The test tubes containing this charge were in each case incubated for 24 hours and thereafter the degree of turbidity was The absence of turbidity indicated an bacterial At a dosage of the following bacterial cultures were free of coli coli Proteus vulgaris Klebsiella K Klebsiella Salmonella Shigella Enterobacter Serratia Proteus Proteus Pasteurella Brucella Haemophilus influenzae Bordetella Bacteroides s Staphylococcus aureus Neisseria caterrhalis sp Diplococcus moniae Streptococcus pyogenes Enterococcus Lactobacillus Corynebacterium diphteriae nebacterium pyogenes Clostridium Clostridium Borrelia P3eudomonas aeruginosa monas hydrophila Table 1 which ollows shows the of one of the penicillins according to the invention against a broad trum of in animal experiments with white The white of the were infected neally with the type of bacteria indicated in each l Animal experiments with white mice 30 minutes after infection 30 and 90 minutes after infection Pour 30 2 4 hours and 6 hour infection Dose expressed in body administered subcutan 1 mole of penicillin corresponds to x 108 Units As the sodium salt As stated the invention also relates to the use in human and veterinary medicine of the compounds of the The present invention provides a pharmaceutical composition containing as active ingredient a compound of the invention in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 less than except in the presence of a surface active agent The invention further provides a pharmaceutical composition containing as active ingredient a compound of the invention in the form of a sterile or isotonic aqueous The invention also provides a medicament in dosage unit form comprising a compound of the invention either alone or in admixture with a The invention also provides a medicament in the form of tablets lozenges and ampoules or suppositories comprising a compound of the invention either alone or in admixture with the as used in this Specification means physically discrete coherent portions suitable for medical in dosage unit as used in this Specification means physically discrete coherent portions suitable medical administration each containing a daily dose or a multiple to four or to a of a daily dose of the compound of the the medicament contains a daily dose for a a or a quarter of a daily dose will depend on whether the medicament is to be administered once three times or four times a day The pharmaceutical compositions according to the invention for take the form of sprays solutions and emulsions of the active ient in aqueous or granules or The diluents to used in pharmaceutical compositions adapted to formed into capsules and pills include the fillers and and silicic binding carboxymethyl cellulose and other cellulose tine and polyvinyl moisturizing calcium carbonate and sodium agents retarding resorption quaternary ammonium surface active cetyl glycerol adsorptive kaolin and calcium and magnesium stearate and solid polyethylene The capsules and pills formed from the pharmaceutical compositions of the invention can have the customary envelopes and protective which may contain They can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal possibly over a period of The envelopes and protective matrices may be for of polymeric substances or The ingredient can also be made up in microencapsulated form together with one or several of the The diluents to be ueed in pharmaceutical compositions adapted to be formed into suppositories for be the usual or such as polyethylene glycols and fats cocoa oil and high esters with or mixtures of these The pharmaceutical compositions which are creams and gels for contain the usual animal and vegetable cellulose polyethylene silicic talc and zinc oxide or mixtures of these The pharmaceutical compositions which are powders and sprays for contain the usual silicic aluminium calcium and polyamide powder or mixtures of these Aerosol sprays for contain the usual chloro luorohydrocarbons The pharmaceutical compositions which are solutions and emulsions for contain the customary diluents of the exclusion of solvents having a molecular weight below 200 except in the presence of a such as dissolving agents and specific examples of such diluents are ethyl isoproply ethyl ethyl benzyl benzyl propylene dimethyl oils example ground nut tetrahydrofurfuryl polyethylene glycols and fatty acid esters of sorbitol or mixtures parenteral the solutions and emulsions should be if The pharmaceutical compositions which are suspensions can contain the usual such as liquid ethyl propylene agents ethoxylated isostearyl ene sorbite and sorbitane microcrystalline aluminium and tragacanth or mixtures All the pharmaceutical compositions according to the invention can also contain colouring agents and preservatives as well as perfumes and flavouring additions peppermint oil and eucalyptus and sweetening agents The pharmaceutical compositions according to the vention preferably contain about to more preferably from about to of the active ingredient by weight of the total In addition to a compound of the the ceutical compositions and medicaments according to the invention can also contain other pharmaceutically active They may also contain a plurality of compounds of the Any diluent in the medicaments of the present invention may be any of those mentioned above in relation to the pharmaceutical compositions of the present Such medicaments may include solvents of molecular weight less than 200 as sole The discrete coherent portions constituting the medicament according to the invention dosage unit form or not for any of the tahlets lozenges and pills suppositores and Some of these forms may he made up for delayed release of the active such as include a protective envelope which renders the portions of the medicament physically discrete and The preferred daily dose for oral and parenteral administration of the medicaments of the invention is x 10 to 90 x 10 Units of active The production of the pharmaceutical compositions and medicaments is carried out any method known in the for mixing the active with the to form a pharmaceutical composition a and then forming the composition into the medicament This invention further provides a method of combating relief and cure the mentioned diseases in human and which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the of a medicament according to the It is envisaged that these active compounds will be administered parenterally example subcutaneouely or rectally or preferably perorally or Preferred pharmaceutical compositions and medicaments are therefore those adapted peroral and parenteral such as coated and ampoules of injectable Administration in the method of the invention is preferably peroral or In general it has proved advantageous to administer amounts of from to of body weight per day to achieve effective it can at times be necessary to deviate from those dosage and in particular to do so as a function of the nature and body weight of the human or animal subject to be the individual reaction of this subject to the the type of formulation in which the active ingredient is administered and the mode in which the administration is carried and the point in the progress of the disease or interval at which it is to be Thus it may in some cases suffice to use less than the minimum dosage whilst other cases the upper limit mentioned must be exceeded to achieve the desired Where larger amounts are administered it can be advisable to divide these into several individual administrations over the course of the In veterinary the new compounds can be administered with fodder or drinking The invention therefore as a preferred pharmaceutical medicated fodder comprising an animal feedstuff and a pound according to the The following illustrate the production of the compounds of the invention by the process of the Parts given are by weight unless otherwise and the units are the conventional penicillin units mol being equivalent to x 10 Example 1 parts by weight penicillin trihydrate were dissolved in 25 parts volume of 80 strength aqueous by adding amine until a pH value of was part by weight of was added in whilst and the pH was kept at 7 to 8 by adding After the mixture had been stirred further until the pH was 20 parts by volume of water were the tetrahydrofurane was stripped off on a rotary evaporator and the aqueous solution was extracted once with ethyl acetate covered with ethyl acetate and acidified with dilute hydrochloric acid to constant pH whilst cooling with whereupon the penicillin was very largely obtained as crystalline free which was sparingly soluble in water and ethyl acetate and was filtered off and washed with The free acid thus obtained was verted to the sodium salt and worked up as described The ethyl acetate solution which remained in the mother liquor was separated from the aqueous washed with a little dried over and mixed with parts by volume of a solution of sodium in ether containing the mixture was evaporated almost to dryness in the residue was dissolved in a little methanol and the solution was oured into a amount of ether which contained of The product was filtered washed with ether containing methanol and then with pure ether and dried over and paraffin chips in a vacuum part by weight of sodium penicillin formula The penicillin filtered off earlier was dissolved in 10 parts volume of dimethylacetamide 4 parts by volume of sodium solution were added and the mixture was stirred into ether parts The precipitate which separated out was filtered washed with ether containing methanol and then with pure and dried in a desiccator over and paraffin parts by weight of sodium ormula The two fractions of the sodium penicillin salt thus obtained were identical according to the 88 to content was deduced f om the IR and IR bands at Pnd at and The used as starting compound can be produced as 1 4 parts weight of phosgene in 10 parts by volume of absolute were added dropwise over the course of 15 to a vigorously stirred solution of parts by weight of according to Fischer and page 224 in 50 parts by volume of absolute tetrahydrofurane Thereafter the reaction mixture was stirred 3 hours at and a stream of dry air was then passed through the reaction mixture in order to blow out the hydrochloric acid and remnants of The mixture was now evaporated to dryness vacuo on a rotary evaporator and the solid residue was dried over concentrated sulphuric acid at about 12 mm of Melting point recrystallisation pentane C H N CI C H N CI to and to as the symmetrical bands at and Example 2 parts weight of were suspended in 45 parts volume of strength aqueous parts weight of chloride were then introduced whilst stirring and at the same time the pH was kept at means of after the mixture was stirred further until no more amine had to added to maintain the pH of After dilution with about 80 parts by volume of the hydrofurane was removed in a rotary evaporator and the aqueous solution which remained was covered with ethyl acetate and acidified to pH by means of N hydrochloric acid whilst bulk of the penicillin formed then separated out as a crystalline parts by weight 43 of theory of formula 80 C S C H S bands in the carbonyl region and To convert the penicillin into the sodium the penicillin was dissolved at as high a concentration as possible in methanol or the calculated amount of a solution of sodium in ether containing a few per cent of methanol was added and the mixture was then stirred into an amount of The sodium salt formula which precipitated was filtered washed with ether containing methanol and then with and and Example 3 On reacting parts by weight of hydroxybenzylpenicillin trihydrate with part by weight of in the manner described in Example sodium was obtained in 91 content was determined from the IR and spectrum bands at and NMR signals and ppm Minimum inhibitory concentration in the test tube series dilution P3eudomonas aeruginosa Pseudomonas aeruginosa Klebsiella 4 On reacting parts weight of with part by weight of in the manner described in Example sodium lpenicillin was obtained in content was determined the and IR bands at and NMR signals at and ppm Minimum inhibitory concentration Coli Pseudomonas aeruginosa Pseudomonas aeruginosa P Klebsiella Klebsiella Example 5 On reacting parts weight of trihydrate with part weight of in the manner described in Example sodium formula was in 91 content was determined from the at and signals and ppm 6 On reacting parts weight of with part by weight of in the manner described in Example sodium 1 formula was obtained in content was determined from the and NMR IB bands at and 963 signals and ppm On reacting parts weight of trihydrate with part weight of in the manner described in Example sodium formula was obtained in 90 content was determined the and NMR bands at and NMR signals at and ppm Minimum inhibitory concentration Coli G Pseudomonas aeruginosa P Example 3 On reacting parts by weight of with part by weight of rea in the manner in Example sodium me t hy lami carbony methylpenicillin of formula was obtained in 85 content was determined the and IS bands at and NMR signals at and ppm Minimum inhibitory concentration Coli ml Coli C On reacting parts weight of trihydrate with part weight of in the manner descri ed in Example sodium formula was in 91 content was determined the and hands at and signals at and ppm On reacting parts weight of with part weight of in the manner described in Example sodium meth lpenicillin formula was obtained in content was determined from the and NMR IR bands at and signals a and ppm Exam 11 On reacting parts toy weight of trihydrate with part by weight of acid chloride in the manner described in Example sodium formula was obtained in content was determined the and IB bands at and NMR signals at and Example 12 COONa On reacting parts by weight of with part weight of acid chloride in the manner described in Example sodium formula was obtained in 90 content was determined from the and N R bands at and NMR signals at and ppm Example 13 This penicillin was produced as described in Example 2 from parts weight of trihydrate and part by weight of parts by weight of sodium formula 90 signals and ppm of C H N S into C H S Effectiveness against Pseudomonas F Effectiveness against Pseudomonas Effectiveness against coli Effectivenesa against coli C This penicillin was produced as described in Example 2 from parts weight of penicillin trihydrate and part by weight of acid parts by weight of sodium penicillin of formula signals at and ppm Effectiveness against Goli 15 This penicillin was produced as described in Example 2 from parts by weight of and part by weight of acid parts by weight of sodium of formula signals and ppm Effectiveness against Coli Example 16 This penicillin was produced as described in Exanple 2 from parts by weight of and part by weight of parts by weight of sodium formula signals at and ppm Effectiveness against Effectiveness against Coli C against Klebsiella K Effectiveness against insufficientOCRQuality

Claims (9)

1. 43708/2 CLAIMS : 1. Compounds which are penicillins of the following general formula and their salts:- in which:- E A is a X-C0-N- or C- - - group; in which X is hydrogen, an optionally /¾ntro-substituted alkyl radical with up to 10 carbon atoms, an alkenyloxy group with up to 10 carbon atoms, lower alkylamino or di-lower alkylamino group or a phenyl group optionally substituted with libtro and lower alkyl or a group Y is an alkyl group w th up to 4 carbon atoms, Z is a divalent group of one of the following general formulae: in which G is a hydrogen atom or an alkyl radical with up to 3 carbon atoms; E is an oxygen or sulphur atom; B is a hydroxyphenyl or cyclohexadienyl group * 43708/2 indicates that when Z is one of the asymetric groups given, it can only be oriented in the direction shown by the ar^ow.

2. Compounds according to claim 1 in which A is the group of the formula:- 0 HN li-

3. Compounds according to claim 1 in which C* is in the D=R configuration.

4. D-a-^L ( 2-Oxo-imidazolidin-l-yl)-carbonylamino]-jp-hydroxy-benzylpenicillin: and its salts.

5. D-a-L ( 2-0xo-imidazolidin-l-yl)-carbonylamino]-2, 5- dihydro-benzylpenicillin: and its salts.

6. D-a-(3-Acetyl-3-methyl-ureido)-jo-hydroxy-benzyl- penicillin: 43708/2 and its jsalts. .

7. D x-(3-Methylaminocarbonyl-3-methyl-iireido)-j2-hydroxy- benzylpenicillin: and its salts.

8. D ^-(3-dimethylamino-carbonyl-3-methyl-ureido)-£-hydroxy-benzylpenicillin: and its salts. ft. ! D-a-L3-(Piperidin-l-yl-carbonyl)-3-methyl-ureido]-£-hydroxy-benzylpenicillin: and its salts. 43708/2 10. D-a-L (2-0xo-pyrrolidiri-l-yl)^Gai*bonylamino]-£-hydroxy- benzylpenicillin: and its salts. 11. D-a-L (2-Oxo-3-methyl-imidazolidin-l-yl)-carbonylamino]-jo-hydroxy-benzylpenicillin: and its salts. 12. D-a-(3-Dimethylaminocarbpnyl-3-n-propyl-ureido)-J2- hydroxy-benzylpenicillin: and its salts. 13 D-a-(3-Acetyl-3-methyl-ureido)-a-(1,4-cyclohexadien-l-yl)■ methylpenicillin: 43708/3 1 . D-a-(3-Methylaminocarbonyl-3-niethyl-ureido)-a-(l,4- cyclohexadien-l-yl)-:nethylpenicillin: and its salts. 15. D-ct-(3-Diniethylanjinocarbonyl-3-niethyl~ureido)-a- (l,4~cyclohexadien-l-yl)-Eiethylpenicillin: and its salts. 16 D-a-[3-(Piperidin-l-yl-carbonyl)-3-methyl- reidoJ-a-(1,4-cyclohexadien-l-yl)-methylpenicillin: and its salts. 43708/3 17; D-a-L ( 2-Oxo-pyrrolidin-l-yl)-carbonylamino]-a- ( 1, 4- cyclohexadien-l-yl)-methylpenicillin: and its salts. 18. D-a-L ( 2-Oxo-3-methyl-imidazolidin-l-yl)-carbonyl amino-tr-i 1, 4-cyclohexadien-l-yl)-methylpenicillin: ) and its salts. 19 , D-a-(3-Dimethylaminocarbonyl-3-n-propyl-ureido)-a ( 1 , 4-cyclohexadien-l-yl)-methylpenicillin: and its salts. 20 . Compounds according to Claim 1 that are hereinbefore expressly mentioned in Examples .1 and 2 or 3 - 16. 21. A process for the production of a compound according _ — I . to any of claims 1 to.20 in which:- (a) a compound of the general formula:- is reacted with a compound of the general formula:- X_CO-N-CO-W nT. ' E N-CO-W (VI) (VII) in which general formulae II, VI and VII, B, C*, E, X, Y and Z are as defined in claim 1 and V/ is a halogen atom, an azide group, or a group of one of the following general formulae:- -S- Lower Alkyl. 0 (b) a compound of the general formula:- is reacted with a compound of the general formula VI or VII given in (a) above, and the fragment -^C - is hydrolytically G G . split off as the carbonyl- compound G^COuG; in which general formulae III, VI and VII, B, C*t E, G, X, Y and Z are as defined in (a) above; 43708/2 kin which B is as defined in claim 1 and can also trialkylsilyl group of the general formula:- in which R , R and R are identical or different lower alkyl groups] is reacted with a compound of the general formula VI or VII given in (a) above to produce a product that is either the desired compound of claim 1 or (where in B is a trialkylsilyl group) an intermediate which is then hydrolysed to remove the trialkylsilyl group or groups and produce a 43708/ 3 required compound of Claim 1 in which B is a hydroxyphenyl radical in which general formulae IV, V,VI and VII, B, C*, E, X, Y and Z are as defined in Claim 1 except as stated t immediately above for B. 22. A process according to claim 2l'(a) or (b) in which the reaction is carried out in a solvent at -20 to +50°C in the presence of a base. 23 A process according to claim 21(c) in which the compound of general formula IV or V is reacted with the compound of general formula VI or VII in a hydroxy1-group-free solvent in the absence of water and in the presence of a tertiary amine or a sterically-hindered secondary amine at -20 to +50°C. 24 A process for the production of a compound according to any of claims 1 to 20' substantially as hereinbefore described in Example 1 or 2. 25. A process for the production of a compound according to any of claims 1 to 20 substantially as hereinbefore described in any of Examples 3 to 16. 26. . Compounds according to Claim 1 whenever produced by a process according to any of Claims 21 to 25. 27. . A pharmaceutical composition containing as an active ingredient a compound according to any of Claims 1 to 9 and 26 in admixture with a solid or liquified gaseous diluent or in admixture wj.th a liquid diluent other than a solvent of molecular weight less than 200 except in the presence of a surface-active agent. 2 f. A pharmaceutical composition containing as an active ingredient a compound according to any of Claims 1 to 20 and 26 in the form of a sterile or isotonic aqueous solution. 2

9. A pharmaceutical composition according to Claim 27 or 28 containing from 0.5 to 95 % by weight of active ingredient. • 43708/3 31. A pharmaceutical composition according to any of Claims 27 to 30 substantially as hereinbefore described. ' 32. A medicament in dosage unit form comprising a com-" pound according to any of Claims 1 to 20 and 26 either alone or in admixture with a diluent. 33. A medicament in the form of tablets, pills, dragees, capsules, ampoules or suppositories comprising a compound according to any of Claims 1 to 20 and 26 either alone or in admixture with a diluent. 34. A medicament in dosage unit form as claimed in Claims 32 and 33 substantially as hereinbefore described. 35. A method of combatting bacterial infection in non-human animals which comprises administering to the animals an active compound according to any of Claims 1 to 20 and 26 either alone or in admixture with a diluent or in the form of a medicament according to Claim 32 or 33. 36. A method according to Claim 35 in which the active compound is administered in an amount of 25,000 to 1 x 10^ U/kg/day. 37. A method according to Claim 35 or 36 in which the active compound is administered perorally. 3f. A method according to Claim 35 or 36 in which the active compound is administered parenterally . 39. A method according to Claim 36 substantially as hereinbefore described.