IE42666B1

IE42666B1 - Deoxyclavulanic acid and deoxyisoclavulanic acid and derivatives thereof

Info

Publication number: IE42666B1
Application number: IE628/76A
Authority: IE
Original assignee: Beecham Group Ltd
Priority date: 1975-04-14
Filing date: 1976-03-25
Publication date: 1980-09-24
Also published as: DK144066C; SE7604287L; ATA215576A; HU175444B; MX3453E; GR58256B; CH602742A5; ES446468A1; AU497577B2; IE42666L; FR2336130B1; LU74749A1; AU1302076A; CA1074802A; PT64897B; DK144066B; DK156576A; NO761241L; AR208773A1; FR2336130A1

Abstract

A N T I B I O T I C S The compounds of the formula: and salts and esters thereof are useful agents for the treatment of bacterial infections either alone or in combination with a penicillin or cephalosporin derivative. The proceeding compounds may be prepared by the hydrogenation of a compound of the formula: wherein R is a hydrogen atom or an acyl group or a salt or ester thereof.

Description

PATENT APPLICATION BY (71) BEECHAM CROUP LIMITED, A BRITISH COMPANY, OF BEECHAM HOUSE, GREAT WEST ROAD, BRENTFORD, MIDDLESEX, ENGLAND. 43666 The present invention relates to novel S-lactam containing compounds useful in anti-bacterial therapy, to compositions containing these novel compounds and to the method of their preparation.

Belgian Patent No. 327,926 discloses inter alia that the compound of the formula (I): and its salts and esters possess anti-bacterial and S-lactamase inhibitory activity. The compound of the formula (I) is designated clavulanic acid. Acylated derivatives of the above compounds are disclosed in Netherlands Patent Application No. 75/12348 and West German Patent Application No.2,555,626 discloses inter alia isoclavulanic acid and its salts and esters which compound isoclavulanic acid has the formula (II):'' - 2 42666 Isoclavulanic acid and its salts and esters also have antibacterial and 3-lactanase inhibitory activity. A further group of compounds v/ith useful anti-bacterial and fi-lactamase inhibiting properties has now been discovered.

Accordingly the present invention provides the compounds of the formula (III): (III) and salts and esters thereof.

The stereochemistry at C-2 and C-5 of the compounds of formula (III) is the same as that found in naturally occurring penicillins.

The two isomeric acids of the formulae (IV) and (V): (IV) (V) 436C6 are therapeutic agents and are useful intermediates in the formation of their esters but in general their pharmaceutically acceptable salts are more favoured because of their improved stability. The compound of the formula (IV) is designated herein as deoxyclavulanic acid and the compound of the formula (V) is designated herein isodeoxyclavulanic acid.

In general deoxyclavulanic acid and its derivatives form a more favourable aspect of this invention than does isodeoxyclavulanic acid and its derivatives because of their generally . » more facile production.

Suitable salts of the compounds of the formula (III) include conventional pharmaceutically acceptable salts such as the sodium, potassium, calcium, magnesium, ammonium and conventional substituted ammonium salts for example those used with benzylpenicillin such as the 1-ephenamine, procaine and benzathine salts.

Particularly suitable salts of deoxyclavulanic acid and isodeoxyclavulanic acid include their sodium and potassium salts.

Preferred salts of this invention include those of the formulae (VI) and (VII); - 4 42666 The sodium salt of deoxyclavulanie acid is a particularly suitable compound of this invention.

/’ Non-pharmaceutically acceptable salts of the compounds of the formula (III) can also be useful as they can serve as intermediates Jn the preparation of esters of the compounds of formula (III); for example, by reaction with pivaloyloxyaethyl chloride to give a useful antibacterial agent.

Suitable esters of the compounds of formula (III) include those of the formula (VIII): H I t co2r wherein R is an organic group such that the alcohol ROH is pharmaceutically acceptable.

It is envisaged that the esters of deoxyclavulanie acid and deoxyisoclavulanic acid owe much of their antibacterial activity to their ability to act. as pro-drugs for deoxy15 clavulanic and isodeoxyclavulanic acids and their salts. Thus preferred esters are those which are convertible to the corresponding acid or its salts under physiological conditions. - 5 426C6 Particularly suitable esters of the compounds of the formula (VIII) include those of the formula (IX): wherein R is as defined in relation to formula (VIII).

Suitable groups R for inclusion in the compounds of 5 formula (VIII) include alkyl, alkenyl, alkynyl, aryl or arylalkyl any of which may be substituted if desired.

In order not to increase the molecular weight to an unreasonable extent, groups R do not normally include more than 16 oarbon atoms, more suitably not more than 12 carbon atoms and most suitably, not more than 8 carbon atoms. Generally the COgR group is such that the compound of the formula (VIII) has a molecular weight of not more than 400. - 6 436G6 Preferably, the group '< h; nationally derived from an alcohol JioH which .is phiutiaceuticaily acceptable. Suitable groups R include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, allyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclohexadienyl, methylcyclopentyl, methylcyclohoxyl, cyclopentylmethyl, c.yclohexylmethyl, benzyl, benzhydryl, phenylethyl, naphthylmethyl, naphthyl, phenyl, propynyl, tolyl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, acetylmethyl, benzoylmethyl, 2-methoxyethyl, p-chlorobenzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, m-chloi’obenzyl, 6-methoxynaphthyl~2-methyl, p-chlorophenyl, p-methoxyphenyl or g-2'-pyridylethyl.

Suitable readily in-vivo hydrolysable ostor groups COgR include but are not limited to groups such as those represented by the sub-formulae (a) and (b): - CO - 0 - - X - CO - A3 (a) wherein A-j is a hydrogen atom or a methyl group; Ag is a hydrogen atom or a methyl, ethyl or phony! group; Aj is an alkyl or alkoxyl group of 1-6 carbon atoms or a phenyl or benzyl group; A/( is -CKgCHg-, -CHsCH-, - 7 and X is an oxygen or sulphur atom. Mont suitably X is an oxygen atom and Ag is a methyl or t-butyl group and A^ is a phenylene group.

A further particularly suitable sub-group of esters of formulae (Vl'II) are those wherein R is ί group 1 ρ 7) 1 R or CHR R·^ wherein R is a hydrocarbon group of 1 to 9 carbon atoms optionally substituted by halogen, lower alkoxy, lower acyl, hydroxy or lower acyloxy and R and R are each an optionally substituted phenyl group.

•The term 'lower* used herein means the group contains up to 6 carbon atoms. The term 'optionally substituted phenyl' includes a phenyl group and a phenyl group substituted by a halogen ato'm or a lower alkyl or lower alkoxy group.

An alternative aspect of the present invention provides a phaimaceoileal composition which contains a compound of the formula (XII) or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier. Favourably such compositions contain a pharmaceutically acceptable salt or in-vivo hydrolysable ester of a compound of the formula (III) More suitably, the pharmaceutical composition of this invention will contain a pharmaceutically acceptable salt of the compound of the formula (III). The compositions of this invention will normally be adapted for administration to humans and other mammals, for example, in conventional modes of treatment of diseases of the urinary tract, respiratory system and soft tissues as well as diseases such as otitis media in humans and mastitis in domestic animals .

Suitable forms of the compositions of this invention include tablets, capsules, creams, syrups, suspensions, solutions, reconstitutable powders and sterile forms suitable for injection or infusion . Sueh compositions may contain conventional pharmaceutically acceptable materials such as diluents, binders, colours, flavours, preservatives and disintegrants in accordance with conventional pharmaceutical practice and the arts of formulating antibiotic compositions.

Compositions adapted for oral administration may also comprise a buffering agent or may be protected from gastric juice in a conventional manner if so desired.

The compound of formula (XIX) or a salt or ester thereof may be present in the composition as sole therapeutic agent or it may be present together with other therapeutic agents such as a penicillin or cephalosporin derivative. Suitable penicillin and cephalosporin derivatives for inclusion in such compositions include not only those known to be susceptible to β-lactamases .0 but also those which have a degree of intrinsic resistance to B-lactamaSes. Thus, suitable penicillin and cephalosporin derivatives for 'inclusion in the composition of this invention include benzylpenicillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, hetacillin, ampicillin, amoxycillin, ticarcillin, cephaloridine, cephalothin, cephalexin, cephaloglycin, cephamandole and in-vivo hydrolysable esters of such compounds such as the phenyl, tolyl and 5-indanyl esters of carbenicillin and ticarcillin, the acetoxymethyl ester of benzylpenicillin and the acetoxymethyl, pivaloyloxymethyl and phthalidyl esters of ampicillin, amoxycillin, cephaloglycin, cephalexin or mecillinam or a salt of a preceding compound. - 10 4 3 66 6 Y/hen present in a pharmaceutical composition together with a ij-lactam antibiotic, the ratio of the compound of formula (III) or its salt or ester present to the penicillin or cephalosporin derivative present may he frcm, for exanple, 20:1 to 1:5, such as 10 : 3 to 1 : 3, and advantageously may be 5:1 to 1 : 2, for example, 3 : 1 to 1 : 1.

The total quantity of antibacterial agents present in any unit dosage form will normally be between 50 and 1500 mg and will usually be between 100 and 1000 mg, However, injectable or infusable compositions may contain greater quantities if desired, for example, 4 g or more of active material. Normally, between 50 and 6000 mg of the compositions of this invention will be administered each day of treatment but more usually between 500 and 3000 mg of the composition of the invention will be administered per day. In general the equivalent of not more than 2000 mg of a compound of the formula (III) will be administered per day, for example, 100 - 1000 mg.

In a further aspect this invention provides synergistic compositions which contain a compound of the formula (III) or a pharmaceutically acceptable salt or ester thereof and ampicillin, amoxycillin or a pro-drug for ampicillin or amoxycillin. Such compositions are preferably adapted for administration to humans and contain 50 - 500 mg of a salt or in-vivo hydrolysable ester of a compound of the formula (III) and 200 - 1000 mg of the penicillin. Particularly suitable - ll 42665 forms of the penicillins for inclusion in orally administrable forms of such compositions include ampicillin trihydrate, amoxycillin trihydrate, anhydrous ampicillin, ampicillin pivaloyloxymethyl ester and ampicillin phthalidyl ester or an a addition salt such as the hydrochloride of said esters. Particularly suitable forms of the penicillins for inclusion in injectable forms include, sodium ampicillin and sodium amoxycillin, sodium ampicillin being preferred. Such compositions may be used in treating infections of the urinary tract and respiratory tract and are particularly useful in treating infections due to strains of Klebsiella aeroginosa, Proteus, or Ξ. coli.

In a further aspect this invention provides synergistic compositions which contain a compound of the formula (III) or a pharmaceutically acceptable salt or ester thereof;and 25 carbenicillin or ticarcillin or a salt thereof, the phenyl α-ester of carbenicillin or ticarcillin; the 5-lndanyla-ester of carbenicillin, the*tolyla-ester of ticarcillin, or a salt of said penicillinresters. Such compositions are preferably adapted for administration to humans and contain 50 to 1500 mg of a salt or in-vivo hydrolysable ester of a compound of the formula (III) and 200 to 1500 mg of the penicillin. Such compositions may be used in treating infections of the urinary tract. 42SG6 The preceding compositions preferably contain a pharmaceutically acceptable salt of a compound of the formula (III) such, as the sodium or potassium salt, for example, a compound of the formula (VI), In a further aspect this invention provides a process for the preparation of a compound of the formula (III) as hereinbefore defined or a salt or ester thereof which process comprises the hydrogenation of a corresponding compound of the formula (X) or a salt or ester thereof wherein Rg is a hydrogen atom or an acyl group, and thereafter isolating the desired compound.· It is frequently particularly convenient to use a compound of the formula (X) wherein Rg is a hydrogen atom. It is also frequently convenient to use a compound of the formula (X)' in the form of a salt thereof.

Normally, such a reaction takes place in the presence of a transition metal containing catalyst such as palladium or platinum oxide. A particularly suitable catalyst is palladium on charcoal, for example, 10% palladium on charcoal. - 13 The catalyst employed ic suitably in highly active form, for example, the sort obtained by using a fresh batch of catalyst.

Most suitably the weight of catalyst (as total 10% palladium 5 and charcoal or the equivalent) present is at least 1/3 of the weight of the compound of formula (X) or salt or ester present. It is advantageous to have at least as much catalyst present as compound of formula (X) present, especially for those compounds wherein Rg is H.

The process of this invention normally takes place at a non-extreme temperature; for example, the reaction may take place in a lower alkanol at a temperature of -10°C to +50°C, more usually from 0°C to 25°C, for example, from 5°C to 20°C.

The process of this invention normally takes place in an inert solvent such as a lower alkanol, water or an aqueous alkanol. Most suitably the solvent employed is a lower alkanol such as methanol or ethanol. For those compounds of the formula (X) wherein Rg is H water miscible ethers such as tetrahydrofuran are also suitable solvents but such ether solvents are not generally suitable for use when Rg is an acyl group.

An elevated, medium or low pressure of hydrogen may be used in this reaction. Generally, it is preferred to use an atmospheric or slightly super atmospheric pressure of hydrogen - 14 42GC6 A preferred form ef the process of this invention comprises the hydrogenation of clavulanic acid or a salt or hydrogenisable ester thereof in the pretence of a palladium catalyst. Such a process leads to the preparation of a compound of the formula (IV) or a salt thereof. If a salt is required and the clavulanic acid is not already in salt form a base such as sodium bicarbonate may be included άη the reaction medium.

Hydrogenation of isoclavulanic acid or a derivative thereof 10 frequently leads to a deoxyisoclavulanic acid derivative contaminated with a corresponding deoxyclavulanic acid derivative. A purer product may then be obtained by chromatography.

The nature of an acyl group Rg which may be present in a 15 compound of the formula (X) is relatively unimportant as long as it does not lead to the rapid breakdown of the compound of formula (X). Suitable acyl derivatives are described in Netherlands Application No. 75/12268, Particularly suitable acyl groups Rg contain up to 16 carbon atoms and may be optionally substituted by groups such as halogen, lower alkoxy, lower alkoxycarbonyl, lower acyloxy or hydroxy Most suitably such acyl groups are unsubstituted or substituted by non-reactive groups only.

Esters of the compounds of formula (ill) may be prepared by ?5 the reaction of a compound of the formula (III) or a salt thereof with an alcohol ROH or a compound of the formula RQ where Q is a good leaving group such as a chlorine, bromine or iodine 426C6 atom or an activated ester group or a sulphonic ester group such as a mesylate or tosylate group. Alternatively, the acid, of the formula (III) may be treated with a diazocompound such as diazomethane or viith an alcohol ROH in the presence of a dehydrating agent such as a carbodiimide .

The reaction with RQ is normally carried out in an organic solvent of relatively high dielectric constant such as dimethylformamide, acetone» dioxane or tetrahydrofuran and at a non-extreme temperature such as -5°C to 100°C, more usually 45°C to 30°C, for example, at ambient temperature.

Tlie reaction of an acid of formula (III) with a diazoalkane is a mild method of making alkyl or aralkyl esters.

The diazotization reaction may he performed under conventional reaction conditions, for example at a non-extreme temperature and in a conventional solvent-. Such reactions are normally carried out at between -5°C and 100°C, more usually from 5°C to 30°C, for example at ambient temperature. Suitable solvents for this reaction include lower alkanols such as methanol and ethanol and solvents such as tetrahydrofuran and dioxane. Ethanol has proved a particularly useful solvent for this reaction.

The reaction of an acid of formula (III) with an alcohol in the presence of a condensation promoting agent will normally 25 take place in an inert organic solvent such as dichloromethane or acetonitrile. This reaction is usually carried out at an ambient or depressed temperature, for example at -10°C to +22°C, more usually -5°C to for example initially at 0°C and thereafter gradually - 16 43666 warming to about 15°C. 'be condensation promoting agent used j.:; normally or:·, which removes water from the reaction mixture. Suitable agents include carbodiimides and carbodiimidazoles. Dicyclohexylcarbodiimide has proved to be a particularly suitable condensation promoting agent for use in this process.

Other less suitable methods of ester formation include (a) removal of the elements of carbon dioxide from a compound of the formula (XI): fcO-O-CO-O-Ry wherein Ry is an inert organic group; and also (b) reaction of a compound of the formula (XI) with alcohol ROH, The compound of the formula (XI) may be prepared by the reaction of a salt of a compound of the formula (III) with Cl.CO.O.Ry or the chemical equivalent thereof. - 17 Salts of tho compounds of the fonnula (III) may be prepared by the hydrolysis of an eater of a compound of the formula (ITI, Generally this may be brought about by keeping the ester of the compound of formula (III) in an aqueous medium maintained at pH of 7 to 9 for up to one hour. Certain reactive esters such as the pivaloyloxymethyl, acetoxymethyl and phthalidyl esters. hydrolyse in a few minutes when maintained in an aqueous medium a I: a pH of 6 to 8.

The following Examples illustrate the invention: - 18 42606 EXAJIPL" 1 Sodium Dnpxyclovpi Benzyl clavulanate (220 mg) in ethanol (20 ml) was hydrogenated over 10% Pd/C (70 mg) and sodium hydrogen carbonate (60 mg) for 60 minutes. The catalyst was filtered, washed with water and then ethanol and the combined filtrates were evaporated. This material was chromatographed on a silica gel column with n-butanol/ethanol/water; 4:1:1^/^ and the fastest moving component was collected. The solvents were removed under low pressures to yield the sodium salt, of deoxyclavulanic aoid.

I.r. (KBr): 1780, 1700, 1605 cm-1; n.m.r. (D20): 1.52 (3H, dd, J 7Hz, J* 1.5Hz); 2.98 (IE, d, J 13Hz, 6S-CH); 3.52 (IH, dd, J 18Hz,. J’ 2.5H2, 6oc-CH); 4.5 - 4.9 (m, obscured by HOD peak); 5.64 (IH, d, J 2.5Hz, 5-CH).

[The sodium salt of clavulanic acid was also obtained from the column on further elution]. - 19 43666 EXAMPLE 2 Sodium L'-oxycl avulanatc COgMa (Vll Benzyl clavulanate (8.25 g) was dissolved in tetrahydrofuran (75 ml). To the solution was added 10% palladium on ’ charcoal (8.25 g) and the mixture was hydrogenolysed at room temperature with vigorous shaking and using 1 atmosphere pressure of hydrogen for 30 minutes. The suspension was filtered and the filtrate was treated with a solution of sodium bicarbonate (2.39 g) dissolved in the minimum amount of water. The solution was concentrated under reduced pressure on a rotary evaporator at room temperature and the residue was triturated with acetone and diethyl ether to give a pale yellow solid (k.7 g}. - 20 426C6 EXAMPLE 5 Sodium Dcoxyclavulan-rbe ch2.o.c6h5 H2, Pd/G NaHCO, Benzyl phenoxyacetylclavulanate (140 mg) was dissolved in ethanol/ethyl acetate (5:1, 6 ml) and sodium bicarbonate (56 mg) and 10% palladium on charcoal (47 mg) were added to the solution. The solution was hydrogenated at ambient temperature (-^ 18°C) for 15 minutes. The catalyst was filtered off and washed well, with water. The filtrate and washings were combined and evaporated to dryness to give a quantitative yield of sodium deoxyclavulanate. Sodium deoxyclavulanate may be separated from the mixture with sodium phenoxyacetate by careful column chromatography using silica gel and eluting with butanol/ethanol/water. (Physical characteristics of product as in Example 1).

The preceding example may be varied by replacing the benzyl phenoxyacetylclavulanate with equivalent amounts of benzyl acetylclavulanate, benzyl a-fphenyloxycarbonyljphenylacetylclavulanate or p-bromobensyl phenoxyacetylclavulanate.

The preceding example may also be varied by replacing the benzyl phenoxyacetylclavulanate with an equivalent amount of benzyl s-fbencyloxycarbonyUphenylacetamidoclavulanate and increasing the amount of sodium bicarbonate to 2 equivalents. 428C6 EXAMPLE 4 p-Bromobonzyl Deoxyclavulanate A solution of p-bromobenzyl bromide (50 mg) was added to a solution of sodium deoxyclavulanate (10 mg) in diffiethylform5 amide (0.5 ml) and the mixture was kept at ambient temperature (about 18°C) for 2 hours. The reaction mixture was fractionated on silica gel eluting with ethyl acetate/ hexane (1:4) to yield p-bromobenzyl deoxyclavulanate (as an oil) on evaporation. i.r. (CHC13): 1790, 1740, 1695 cm-1; N.m.r. (CDCl^): 1.62 (3H, dd, J 7Hz, J' 1.4Hz, CH^); 2.95 (IR, dd, J 17Hz, J' 1.0Hz, 6B-CH); 3-48 (IH, dd, J 17Hz, J» 2.6Hz, 6a-CH); 4.58 (IH, dq, J 7Hz, J' 1Hz, =CHCHj); .03 (IH, dd, J 1.4Hz, J' 1.0Hz, 3-CH); 5-12 (2H, s, COgCHg-); .65 (IH, dd, J 2.6Hz, J' 1.0Hz, 5-CH); 3-38 (4H, ABq, J 8.5Hz aromatic' protons). 42566 The preceding example may be repeated replacing p-brcmobe: yl bromide with an equivalent quantity of methyl iodide·, ethyl bromide, l-broino-2-methoxyethane, pivaloyloxymethyl chloridephthalidyl bromide, l-chloro-2-methy1thioethane, l-chloro-25 phenylsulphonylethane, l-bromononane, 4-methoxybenzylbromide, benzylbromide, benzylchloride or phenacetyl bromide.

EXAMPLE 5 Sodiunt DeoxyiEoclavtilnnate 1. Pd/C + H? χ 2. NaHCO, Benzyl isoclavulanate (50 mg) in letrahydrofuran (0.5 ml) was hydrogenated at room temperature (~ 18°C) and atmospheric pressure using 10% palladium on charcoal (50 mg) as catalyst. After 30 minutes the catalyst was filtered off and an equivalent amount of aqueous sodium bicarbonate added. The solvent was removed by evaporation and the residue triturated with ethanol, acetone and acetone diethyl ether to g: the product as an off-white solid (20 mg). [The n.m.r. spectrum in D^O showed that the title compound was contaminated with sodium deoxyclavulanate]. - 24 EXAMPLE ' Sodium deoxyclavulanate did not appear to produce any overt toxic effects in mice when administered intra-peritoneally at 500 mg/kg.

Tho antibacterial and synergistic properties of sodium deoxyclavulanate are illustrated by tho following in-vitro results: Organism Minimum Inhibitory Concentration of Sodium Deoxyclavulanate (ng/ml) Bacillus subtilis A 62.5 Entcrobacter cloacae Nl 125 Escherichia coli 10418 62.5 Klebsiella aerogenes A 62.5 Proteus rairabilis C 977 125 Pseudomonas aerurinosa A 1000 Salmonella tynhinurium CT10 125 Serratie marcescens US 3S 125 Stanh. aureus Oxford 15.6 Staph, aureus Russell 31 43SG6 ω ο fi tt r Η ttiJ3 fi P-i bO ri. fi'Ή Ο» fiP Ή & Η ii Η ω •Η γ4 Ο fi •Η £ Λ 05 S f~' < Ο r**» <Η Κ Ο ο 0) ^,q r—I tsD’H fi/tf <~Χ Ο CC α Ο <Η •Η Ο Ρ d ω fi Γ5 Ρ ο β·Η ω -ρ ο fi fi L* op O fi 0) >» ο fi fi O O PO «Η p tt •h 2 ,fi o SM •Η O fi •K OJ a o OJ o I rd .1 in rn o d o 1 CJ • c H co OC o d o o o o O m in Λ H H 0) tt tt fi ο cd c- w Ex: w φ ‘1* ε fi Γ* CQ fi Φ •H Pi ύ. fi 0 fi tt Li h0 fi C’ fi o fi O o 0 fi ο Γ-; 0 H Η 0 > •r·'. X* tr Ρ X fi o Ρ r-‘ CC K Inhibition produced by sodium deoxyclavulanate alone at this concentration

Claims

CLAIMS:

1.A compound of the formula (III): CH.CH. (Ill) or a salt or ester thereof.

2. A compound as claimed in claim 1 which is a compound of the formula (IV): (IV, or a salt or ester thereof.

3. A compound as claimed in claim 1 which is a compound of the formula (V): H (V) or a salt or ester thereof.

4. A salt as claimed in any of claims 1 to 3.

5. A pharmaceutically acceptable salt as claimed in claim 4.

6. A salt as claimed in claim 5 which is a sodium salt.

7. A salt as claimed in claim 5 which is a potassium salt. - 27 5 42SC6 8. A salt as claimed in claim 5 which is a calcium salt. 9. A salt as claimed in claim 5 which is a magnesium salt. 10. A salt as claimed in claim 5 which is an ammonium salt. 11. A salt as claimed in claim 5 which is a substituted ammonium salt used with benzylpenicillin. 12. The compound of the formula (VI): 13. The compound of the formula (VII): 14. A compound as claimed in claim 1 of the formula (VIII): (VIII) wherein R is an organic group such that the alcohol ROH is pharmaceutically acceptable. - 28 <12 S C ΰ 15. A compound as claimed in claim 14 of the formula (IX): H (IX) wherein R is as defined in claim 14. 16. A compound as claimed in claim 14 or 15 where R is a group suoh that the compound of the formula (VIII) or (IX) has a molecular weight of not more than 400. 17. A compound as claimed in claim 14 or 15 wherein R is methyl. 18. A compound as claimed in claim 14 or 15 wherein R is ethyl. 19. A compound as claimed in claim 14 or 15 wherein R is propyl. 20. A compound as claimed in claim 14 or 15 wherein R is butyl. 21. A compound as claimed in claim 14 or 15 wherein R is pentyl. 22. A compound as claimed in claim 14 or 15 wherein R is hexyl. 23. A compound as claimed in claim 14 or 15 wherein R is heptyl. 24. A compound as claimed in claim 14 or 15 wherein R is octyl. 25. A compound as claimed in claim 14 or 15 wherein R is nonyl. 26. A compound as claimed in claim 14 or 15 wherein R is decyl. 27. A compound as claimed in claim 14 or 15 wherein R is undecyl 28. A compound as claimed in claim 14 or 15 wherein R is dodecyl 29. A compound as claimed in claim 14 or 15 wherein R is allyl. 30. A compound as claimed in claim 14 or 15 wherein R is butenyl 31. A compound as claimed in claim 14 or 15 wherein R is cyclopropyl. 32. A compound as claimed in claim 14 or 15 wherein R is cyclobutyl. 33. A compound as claimed in claim 14 or 15 wherein R is cyclopentyl 29 42SC6 34. A compound as claimed in cyclohexyl. 35. A compound as claimed in cycloheptyl. claim 14 or 15 wherein R is R is claim 14 or 15 wherein 5 36. A compound as claimed in claim 14 or 15' wherein R is cyclohexenyl. 37. A compound as claimed in claim 14 or 15 wherein R is cyclohexadienyl. 38. A compound as claimed in claim 14 or 15 wherein R is .0 methylcyclopentyl. 39. A compound as claimed in claim 14 or 15 wherein R is methyloyclohexyl. 40. A compound as claimed in claim 14 or 15 wherein R is cyclopentylmethyl. L5 41. A compound as claimed in claim 14 or 15 wherein R is cyclohexylmethyl. 42. A compound as claimed in claim 14 or 15 wherein R is benzyl. 43. A compound as claimed in claim 14 or 15 wherein R is 20 benzhydryl. 44. A compound as claimed in claim 14 or 15 wherein R is phenylethyl. 45. A compound as claimed in claim 14 or 15 wherein R is naphthylmethyl. 25 46. A compound as claimed in claim 14 or 15 wherein R is naphthyl. 47. A compound as claimed in claim 14 or 15 wherein R Is phenyl. 48. A compound as claimed in claim 14 or 15 wherein R is 30 propynyl. 4 3 6 C 6 49. A compound as claimed in claim 14 or 15 wherein R is tolyl. 50. A compound as claimed in claim 14 or 15 wherein R is 2-chloroethyl, 51. A compound as claimed in claim 14 or 15 wherein R is 5 2,2 ,2-trichloroethyl • 52. A compound as claimed in claim 14 or 15 wherein R is 2,2,2-trifluoroethyl. 53. A compound acetylmethyl. as claimed in claim 14 or 15 wherein R is 10 54. A compound as claimed in claim 14 or 15 wherein R is benzoylmethyl. 55. A compound as claimed in claim 14 or 15 wherein R is 2-methoxyethyl. 56. A compound as claimed in claim 14 or 15 wherein R is 15 ρ-chlorohenzyl. 57. A compound as claimed in claim 14 or 15 wherein R is p-nitrobenzyl. 58. A compound as claimed in claim 14 or 15 wherein R is p-bromobenzyl. 20 59. A compound as claimed in claim 14 or 15 wherein R is m-chlorobenzyl. 60. A compound as claimed in claim 14 or 15 wherein R is 6-methoxynaphthyl-2-methyl. 61. A compound as claimed in claim 14 or 15 wherein R is 25 p-chlorophenyl. 62. A compound as claimed in claim 14 or 15 wherein R is p-methoxyphenyl. 6 3. A compound as claimed in claim 14 or 15 wherein R is β-2'-pyridylethyl. 42SC6 64. A compound as claimed in claim 14 or 15 wherein R is p-methoxybenzyl. 65. A compound as claimed in claim 14 or 15 wherein the CO 2 R group is of the sub-formula (a) or (b): -CO-O-CA 1 A 2 -X-CO-A 3 (a) -CO-O-CH-A. I I (b) X—C=0 wherein A^ is a hydrogen atom or a methyl group? A 2 is a hydrogen atom or a methyl, ethyl or phenyl group; A^ is an alkyl or alkoxy group of 1 to 6 carbon atoms or a phenyl or benzyl group; and X is an oxygen or sulphur atom. 66. A compound as claimed in claim 65 wherein X is an oxygen atom. 67. A compound as claimed in claim 65 or 66 wherein A 3 is a methyl or t-butyl group. 68. A compound as claimed in claim 65 or 66 wherein A^ is a phenylene group. 69. A compound as claimed in claim 14 or 15 wherein R is a 1 2 3 1 group R or CHR R wherein R is a hydrocarbon group of 1 to 9 carbon atoms optionally substituted by halogen, lower alkoxy, 2 3 lower acyl, hydroxy or lower acyloxy, and R and R are each an Optionally substituted phenyl group. <1 *3 6 C 6 70. A pharmaceutical composition comprising a compound according to any of claims 1 to 69 and a pharmaceutically acceptable carrier. 71. A composition according to claim 70 which also comprises a penicillin or cephalosporin derivative. 72. A composition according to claim 71 which comprises benzylpenicillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, hetacillin, ampicillin, amoxycillin, ticarcillin, cephaloridine, cephalothin, cephalexin, cephaloglycin, cephamandole, the phenyl, tolyl or 5-indanyl ester of carbenicillin or ticarcillin, the acetoxymethyl ester of benzylpenicillin, the acetoxymethyl, pivaloyloxymethyl or phthalidyl ester of ampicillin, amoxycillin, cephaloglycin, cephalexin or mecillinam. or a salt of a preceding compound. 73. A composition according to claims71 or 72 wherein the ratio of the compound of the invention to the penicillin or cephalosporin derivative is from 20:1 to 1:5. 74. A composition according to claim 73 wherein the ratio is from 10:1 to 1:3. 75. A pharmaceutical composition which comprises from 50 to 500 mg of a compound according to any one of claims 1 to 69 and from 200 to 1000 mg of ampicillin, amoxycillin or a pro-drug for ampicillin or amoxycillin. 76. A composition according to claim 75 adapted for oral administration and which includes ampicillin trihydrate, amoxycillin trihydrate, anhydrous ampicillin or the pivaloyloxymethyl or phthalidyl ester of ampicillin or an acid additon salt of said esters. 77. A composition according to claim 75 adapted for administration by injection and which includes sodium ampicillin or sodium amoxycillin. 33 4 3 8 C ΰ 78. A pharmaceutical composition comprising a compound of the formula (III) as defined in claim 1 or a pharmaceutically acceptable salt or ester thereof; and carbenicillin or ticarcillin or a salt thereof, the phenyl α-ester of carbenicillin or ticarcillin, the 5-indanyl α-ester of carbenicillin, the tolyl α-ester of ticarcillin, or a salt of said penicillin esters. 79. A composition according to claim 78 comprising from 50 to 1500 mg of a salt or in-vivo hydrolysable ester of a compound of the formula (III) and from 200 to 1500 mg of the penicillin. 80. A process for the preparation of a compound according to claim 1 which process comprises the hydrogenation of a corresponding compound of the formula (X)ί or a salt or ester thereof wherein Rg is a hydrogen atom or an acyl 5 group, and thereafter isolating the desired compound. 81. A process according to claim 80 wherein Rg is a hydrogen at 82. A process according to claim 80 or 81 where the compound of the formula (X) is in the form of a salt. 83. A process according to any one of claims 80 to 82 in which ) a catalyst is present, the weight thereof being at least 1/3 the weight of compound of formula (X). 4 2 6 C 6 84. A process for the preparation of an ester of the compound of the formula (III) as defined in claim 1 which process comprises esterifying the compound of the formula (III) or a salt thereof. 5 85. A compound as claimed in claim 1 when prepared by the process of any of claims 80 to 84. 86. A compound as claimed in claim 1 as prepared in any of Examples 1 to 5 herein. 87. A process as claimed in any of claims 80 to 84

8. 10 substantially as described in any of Examples 1 to 5 herein.