IE46101B1 - Clavulanic acid ethers - Google Patents

Description

The present invention relates to new ethers of clavulanic acid, to pharmaceutical compositions containing them and to a process for their preparation.

In Belgian Patent No. 847045 corresponding to i Specification No. 44295 it was disclosed that ethers of clavulanic acid could be prepare! by the reaction of a corresponding ester of clavulanic acid with an etherifying agent such as a diazo carpound. It has new been found that certain classes of ethers can be prepared in good yield by a facile reaction. These new ethers, which enhance the anti-bacterial 10 effectiveness of penicillins and cephalosporins, form part of this invention.

Accordingly, the present invention provides the compounds of the formula (I): and salts and esters thereof wherein X is an oxygen or sulphur 9 atom; R xs a hydrogen atom or a lower alkyl group; R is a hydrogen atom or a lower alkyl group which may if desired be joined to R^when R1 is a lower alkyl group; and R3 is a lower alkyl group or an optionally inertly substituted lower, alkyl group or is joined to R2 when R2 is a lower alkyl .group to form an optionally inertly substituted heterocyclic ring of 5- or 6-ring atoms, provided that R1 3 and R are not both hydrogen atans when R is a lower alkyl group.

When Used herein the term lower· means that the group contains not more than 6 carbon atoms and more suitably not more than 4 carbon atans. - 2 4 610 1 When used herein the term inertly substituted means 4 substituted by one or more groups of the formula Ct^OR or OR4 where is a hydrogen atom, a lower alkyl group, a benzyl group or a lower acyl group.

The preferred value for X is the oxygen atom.

Suitable values for R1 include the hydrogen atom and the methyl and ethyl groups.

The preferred value for R1 is the hydrogen atom.

Thus certain favoured compounds of this invention are those of the formula (II): 3 and salts and esters thereof wherein R and R are as defined in relation to formula (I).

For those compounds of the formulae (I) and (II) wherein 13 2 R is not joined to R or R , suitable values for R include tne methyl and ethyl groups, the methyl group bein; especially suitable.

For those compounds of the formulae (I) and (II) wherein 3 3 R and R are not joined, suitable values for R are the methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl groups; more suitable values for R are the methyl, ethyl and propyl groups; and especially 3 suitable values for R are the methyl and ethyl groups, and a preferred value for R3 is the methyl group. 4610 1 For those compounds of the formulae (I) and (IX) wherein 2 3 R and R are joined, particularly suitable values for the 12 3 -CR R -XR moiety are those of the sub-formulae (a) and (b): (a) wherein R is a group R or OR ; R is a group R or OR; Rc is a group R4 or OR4; R^ is a group R4 or OR4; Re is a 4 f 4 4 cr group R or OR ; R is a group R or OR ; and Ra is a group 4 4 R or CHjR wherein any R group can have any value as defined hereinbefore in relation to formula (I). a f Particularly suitable values for R -R include hydrogen 10 atoms, lower alkyl and OR5 groups where R5 is a hydrogen atom or an acetyl, benzoyl or benzyl group and particularly suitable values for R^ include the hydrogen atom, lower alkyl a f or CHjOR group. Favoured values for R -R include hydrogen atoms and lower alkyl groups such as the methyl group.

Preferred values for Ra-Rf include the hydrogen atom.

For those compounds of the formula (I) wherein R1 and 12 R are joined include those wherein the -CR R - moiety represents a cyclopentyl or cyclohexyl group or 4 4 such a group substituted by a R or OR group where R is as defined in relation to sub-formulae (a) and (b).

The compounds of the formula (I) are suitably in the form of a salt such as the lithium, sodium, potassium, calcium, - 4’ Lciu 1 magnesium, ammonium or substituted ammonium salt such as the methylamine, dimethylamine, trimethylamine, pyrrolidine, or other such lower alkylamine, di-hwr .il.i-.yi uiiine, irl-I'wx alkylamine or heterocyclic amine salts.

Particularly suitable salts include the lithium, sodium, potassium and calcium salts.

Preferred salts include the lithium, sodium and potassium salts.

Suitable esters of the compounds of the formula (II) include those of the formulae (III) and (IV): -XR 3 wherein R , R , X and R are as defined in relation to formula (I) and A1 is an alkyl group of 1-8 carbon atoms optionally 4 4 substituted by halogen or a group of the formula OA , OCOA , 4 4 SA cr SO2A wherein A is a hydrocarbon group of up to 6 carbon a toms; A is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl group optionally substituted by halogen or 5 5 5 by a group A or OA where A is an alkyl group of up to 3 carbon atoms; and A is a phenyl group optionally 5 substituted by halogen or by a group A or OA where A is an 20 alkyl group. 3 Particularly suitable values for the CR R -XR moieties in the compounds of this invention include those of the following sub-formulae (a) - (c): - ch(ch3)och3 (a) 5 - CH(CH3)OC2H5 (b) - CH(C2H5)OC2H5 ic) It is believed that the organisms most readily treated by the compounds of this invention are Staphylococcus, Proteus, Klebsiella and Escherichia coii. 4610 1 The present invention also provides pharmaceutical compositions which comprise a compound of the formula (Ϊ) as hereinbefore defined or a salt or ester thereof and a pharmaceutically acceptable carrier.

Most suitably the compound of the formula (I) in the composition of.this invention will be in the form of a pharmaceutically acceptable salt or in-vivo hydrolysable ester.

Preferably the compound of the formula (I) in the composition of this invention will be a pharmaceutically acceptable salt of a compound of the formula (II).

The composition of this invention may be presented orally or parenterally or in. other convenient form» Generally the composition will be adapted for oral administration to humans or for administration by injection to humans Veterinary compositions may also be prepared.

Normally the composition of this invention will be in unit dosage form containing from about 20 mg to 250 mg, for example about 50 or 100 mg, of the active ingredient.

Such compositions will usually be administered from 2 to 6 times daily, for example 3 or 4 times daily so that the daily dose is from about 60 · mg to 1000 mg, more usually from about 200 mg to about 1000 mg.

Desirably the composition of this invention will also comprise a penicillin or cephalosporin. Most suitably the ratio of compound of this invention to penicillin or cephalosporin is from 1:10 to 10:1, more usually 2:1 to 1:5, for example 1:1 to 1:3(by weight).

Suitable penicillins and cephalosporins for inclusion in such compositions include those named In Belgian Specification No. 827926.

Particularly suitable penicillins for inclusion in the compositions of this invention include ampicillin, amoxycillin and their pro-drugs such as their in-vivo hydrolysable esters.

Preferred penicillins for inclusion in the compositions 10 of this invention include ampicillin trihydrate and amoxycillin trihydrate, particularly amoxycillin trihydrate. Other preferred penicillins include the pharmaceutically acceptable salts of amoxycillin.

Penicillins suitable for inclusion in orally 15 administrable compositions of this invention include benzylpenicillin, phenoxymethylpenicillin, propicillin, amoxycillin, ampicillin, epicillin, cyclacillin ani their salts and in-vivo hydrolysable esters and aldehyde and ketone adducts of 20 those penicillins containing a 6-a-aminoacylamido side chain and their salts. Suitable penicillin in-vivo hydrolysable esters include the acetoxymethyl, pivaloyloxymethyl, α-ethOxycarbonyloxyethyl and phthalidyl esters of ampicillin or amoxycillin or the phenyl, tolyl and indanyl α-esters of carbenicillin and ticarcillin and salts thereof.

Suitable aldehyde and ketone adducts of penicillins containing a 6-a-aminoacylamido side chain include the formaldehyde and acetone adducts metampicillin and hetacillin and their salts. Suitable penicillins for inclusion in injectably or infusably administrable compositions include the acceptable salts of benzylpenicillin, phenoxymethylpenicillin, carbenicillin, propicillin, ampicillin, amoxycillin, epicillin, ticarcillin and cyclacillin.

Cephalosporins suitable for inclusion in orally administrable compositions of this invention include cephalexin, cephradine, cephaloglycine and their salts and in-yivo hydrolysable esters and aldehyde and ketone adducts of those cephalosporins containing a 7-a-aminoacylamido side chain and their salts. Suitable cephalosporins for inclusion in the injectable or infusable compositions of this invention Include the salts of cephaloridine, cephalothin, cefazolin, cephalexin, cephacetrile, cephamandole, cephapirin, cephradine and cephaloglycine.

In a further aspect the present invention provides a process for the preparation of a compound of the formula (I) or a salt or ester thereof which comprises the reaction of an ester of clavulanic acid with a compound of the formula (V): 3 Y -CRF - XRJ(v) 3 wherein X, R , R and R are as defined in relation to formula (I) and Y is a readily displaceable atcm or group; ani thereafter if desired converting the thus produced ester into the free acid or a salt or other ester thereof.

Suitable values for Y include I, Br, Cl, OSC^CHy OSO^H^CHj or other similar atoms ctr groups reaiily displaced by a nucleophile.

Particularly suitable moieties Y include bromine and chlorine atoms.

The etherification reaction will normally be effected in the presence of a base of low nucleophilicity such as 2, 4, 6-collidine, potassium carbonate, sodium bicarbonate or 2,6lirtidins.

The etherification will normally take place at a non-extreme temperature such as -20° to 3O°C, for example about 0° to 2O°C.

The solvent used for the reaction may comprise dichloromethane, chloroform, dimethylformamide or tetrahydrofuran, In an alternative process aspect, this invention provides a process for the preparation of compounds of the formula (I) wherein X is an ogygen atcm and R^ is a hydrogen atom, or a salt or ester thereof wherein Rn contains at least 6101 carbon atoms and is optionally joined to R which process comprises the reaction of an ester of clavulanic acid with a compound of the formula (VI): R^C = CH - O - R3 (VI) wherein RhR1CH 2 3 is a group R , and R is as defined in relation to formula (I); and thereafter if desired converting the thus produced ester into the free acid or salt or other ester thereof.

Most suitably R is a hydrogen -atom. i 3 Most suitably R is a hydrogen atom or is joined to R . Particularly suitable compounds of the formul-a (VI) (VII) wherein R^, Rc, R^, R^ and R^ are as defined in relation to sub-formulae (a) and (b).

Normally this reaction will take place in the presence of catalytic quantities of an acid or acid precursor 3uch aa HCl, POClg, p-toluenesulphonic acid and iiy . 46101 In another process aspect this invention also provides a process for the preparation of a compound of the fonnula (I) wherein X is an oxygen atan and R1 is a hydrogen atom, or a salt or ester thereof which process comprises the reaction of an ester of clavulanic acid with a ccsrpcund of the fornula (IX): R5 - 0 - CHR2 -OR3 (IX) 3 wherein R and R are as defined in relation to formula (I) and R3 is a tertiary alkyl group of 4 - 6 carbon atoms; and thereafter if desired converting the thus produced ester into the free acid or a salt or other ester thereof.

A particularly suitable group R3 is the t-butyl group. 3 2 3 Favourably R and R are linked so that the -CHR -OR 3 moiety is a heterocyclic ring. When R and R are not linked it is more suitable that R3 and R3 each represent 5 3 the same group, for example R and R each represent a methyl or ethyl group.

Most suitably the reaction utilizes an excess of the compound of the formula (IX). Generally at least 1 molar excess and preferably 2-5 molar excess of the compound of the formula (IX) is employed. If the compound of the formula (IX) utilized is a volatile liquid it may be used as a solvent.

The present invention also provides a process for the preparation of the compounds of the formula (I) or 25 a salt thereof which process comprises the de-esterification of a corresponding ester of a compound of the formula (I). 4S10i Such de-esterification processes may involve hydrolysis or hydrogenolysis. Thus, for example an ester may be subjected to mild base hydrolysis to yield a salt of the compound of the formula (I) or alternatively a hydrogenolysable ester may be catalytically hydrogenated to yield the free acid or, if a base is present or added later, a salt* More specifically a lower alkyl ester such as a methyl ester may be hydrolysed at pH 7-10 by the slow addition of equivalent of base or a benzyl, methoxybenzyl, nitrobenzyl or like ester may be hydrogenated in the presence of a transition metal catalyst such as palladium on charcoal optionally in the presence of a base such as NaHCOj, Na2CO3, KHCO-j, K2CC>3, Li2CO3 or the like.

This invention also provides a process for the preparation of esters of the compounds of the formula (I) which process comprises the esterification of the compound of the formula (I) or a salt thereof.

Thus a compound of the formula (I) may be reacted with a diazo compound or a salt of the compound of the formula (I) may be reacted with a reactive halocompound or the like.

The following Examples illustrate the invention: 46ΐθ i To a solution of p-methoxybenzyl clavulanate (elO) (lgm) and vinyl n-butyl ether (1ml) in ethyl acetate (10 ml) was added p-toluenesulphonio acid (50 mgs). After stirring for 30 mins at room temperature the mixture was passed through a short column of Kieselgel G using ethyl acetate as eluent. The solvent was evaporated, and the product isolated by column chromatography (Kieselgel G. 1:1 ethyl acetate: cyclohexane) to yield the title compound (0.848 g). v (film) 1805, 1750, 1700cm-1. 6(CDC1,) IuaX j 8.0-9.0 (3H, triplet, J = 7Hz) , 1.26 (3H, doublet, J = 6Hz) 1.10-1.70 (4H multiplet), 2.97 (IH, doublet J = 17Hz), 3.20-3.55 (3H, multiplet), 3.74 (3H, singlet), 4.0-4.2 (2H, multiplet), 4.45-4.75 (IH, multiplet), 4.75 (IH, triplet), 4.99 (IH, singlet), 5.07 (2H, singlet), 5.59 (IH, doublet, J = 3HZ) , 6.80 (2H, doublet, J = 8Hz) , 7.20 (2H, doublet J = 8ΗΖ) 6101 Example 2 Benzyl 9-0-tetrahydropyran-21-yl clavulanate (el2> Benzyl clavulanate (el) (1.0 g) in benzene (5 ml) and dihydropyran (4 ml) was treated with 1 drop of BF3-ether complex and stirred overnight. The solvents were evaporated In vacuo and the residue subjected to column chromatography on silica gel using ethyl acetate and cyclohexane as eluents. After evaporation of the solvent the title compound (el2) was obtained (1.63 g) as an oil which was judged to be about 80% pure.

(Contaminant presumed to be polymers derived from the pyran). υ „ (liquid film), 1805, 1755, 1700 cm1, max 6(CDC13): 1.0 - 2.1 (excess H, br.m, 3',4',5'-¾), 2.97 (1H, d, J 17Hz, 6-8-CH), 3.41 (1H, dd, J 2.5 and 17Hz, 6-a-CH), 3.6-3.95 (excess H, m, 6'-CH2), 3.95 - 4.4 (2H, m, 9-CH2), 4.52 (1H, br,s, 2'-CH), 4.79 (1H, br.t, J 7.5Hz, 8-CH), 5.03 (1H, s, 3-CH), 5.12 (2H, s, PhCH2), 5.60 (1H, d, 2.5Hz, 5-CH) and 7.27 (5H, s, CgHg).

Example 3 Lithium 9-0-tetrahydropyran-2-ylclavulanate Benzyl 9-0-tetrahydropyran2-ylclavulanate (el2) (1.0 g) dissolved in tetrahydrofuran (1 ml) and water (0.05 ml) was hydrogenated over 10% palladised charcoal (0.3 g) during 45 min. to yield a solution of the corresponding acid (el3). The catalyst was removed, the filtrate v/as diluted with an equal volume of water and titrated to pH 7.0 with 1.0 M lithium hydroxide solution. The solution was evaporated to a syrup, ml acetone added, re-evaporated, triturated with acetone (30 ml), filtered off, washed with acetone and ether and air-dried, to yield the title compound (el4) 0.46 g. vmax (nujol mull) 1783, 1790, 1700, 1620, 1625 cm \ 6(D2O) 1.16 - 1.6 (6H, br.m, 3’,4',5'-CH2), 2.89 (1H, d, J 17Hz, 60-CH), 3.39 (1H, dd, J 17 and 3Hz, 6a-CH), 3.55 - 3.91 (2H, m, 6'-CH2), 4.06 (2H, d, J 8Hz, 9-CH2>, 4.5 - 4.9 (3H, m, 2'-CH, 8-CH, 3-CH), 5.55 (1H, d, J 3H±, 5-CH). 6101 Example 4. 4-Methoxybenzyl 9-0-tetrahydrofuran-2-ylclavulanate (elO) FF CH. 2ch2c6h4och3 (el5) A crystal of p-toluenesulphonic acid was added to a solution of 4-methoxybenzyl clavulanate (elO) (3.19 g, 0.1 mole) and 2-tert-butoxytetrahydrofuran (4.32 g, 0.3 mole) in dry dichloromethane (30 ml) and the mixture was stirred at room temperature for 15 min. The mixture was washed with aqueous sodium bicarbonate (50 ml) and then dried amd evaporated to give the title compound (elS) (3.8 g) , υ „ (liquid film) 1805, 1750, 1700, 1250, 1180, and 1025 cm1, 8(CDC13) 7.20 (2H, d, J = 9Hz, ArH), 6.80 (2H, 9ΗΖ, ArH), 5.59 (IH, d, J = 2.5 Hz, 5-CH), 5.08 (2H, s, CH2Ar), 5.00 (IH, s, 3-CH) 5.10-5.00 (IH, m, 2J-CH) , 4.65 (IH, t, J = 7Hz, 8-CH), 3.75 (3H, s, 0¾) , 3.40 (2H, dd, J = 17 Hz, J' = 2.5 Hz, 6«-CH), 2.99 (IH, d, J = 17 Hz, 6β-CH), and 1.6-2.0 (4H, m, 3'and 4'-CH2). 1/ Example 5.

Sodium 9-0-tetrahydrofuran-2-ylclavulanate p-Methoxybenzyl 9-0-tetrahydrofuran-2-ylclavulanate (el5) (1.46 g) and sodium bicarbonate (0.315 g) in tetrahydrofuran/water (5:1,- 30 ml) was hydrogenated at room temperature and pressure in the presence of 10% palladised charcoal (0.5 g) for 30 minutes. The mixture was filtered and the solid washed with a little water anil the combined liquids evaporated to remove the tetrahydrofuran. The aqueous solution was extracted with ethyl acetate (20 ml) and the aqueous phase freeze dried to yield the title compound (0.9 g). vmax (nujol mull), 1785, 1695, 1615 (broad) cm-1. v__„ (KBr), 1785, 1693, 1615 (v. broad) cm ΠΙαΧ δ(B20) 1.86 (4H, m, 3' and 4'-CH2), 3.02 (IH, d, J 17Hz, 68-CH), 3.51 (IH, dd, J 17 and 2.5 Hz, 6 '-CH2), 4.11 (2H, d, J 8Hz, 9-¾) , 4.82 (IH, t, J 8H2, 8-CH), 4.90 (IH, s, 3-CH), 5.20 (IH, m, 2'-CH), and 5.66 (IH, d, J 2.5Hz, 5-CH). 6101 Example 6.

Benzyl 9-0-(1-ethoxy) prop-l-ylclavulanate To a stirred solution of benzyl clavulanate (e 1) £573 mg) and ethyl propenyl ether (0.3 ml) in ethyl acetate (10 ml) was added p-toluenesulphonic acid (5 mg) . The mixture was stirred at room temperature for 1¾ hours and then passed through a short column of Kieselgel, eluting with ethyl acetate. After evaporation of the solvent the product was isolated by column chromatography using gradient elution (Kieselgel 3:1 cyclohexane:ethyl acetate going to 1:1 cyclohexane:ethyl acetate) to yield benzyl 9-0-(1-ethoxy)prop-l-ylclavulanate (e 17) (601 mg), v max (film) 1805, 1750 and 1700 cm-1, δ (CDC13) 0.88 (3H, t, J = 7Hz), 1.17 (3H, t, J = 7Hz), 1.60 (2H, broad quintet, J = 7Hz), 2.99 (IH, d, J = 17Hz), 3.44 (IK, dd, J = 3 and 17HZ), 3.54 (2H, q, J = 7Hz), 4.0 - 4.2 (2H, m), 4.36 (IH, t, J = 6Hz), 4.79 (IH, broad t, J = 7Hz), .05 (IH, s), 5.15 (2H, s), 5.63 (IH, d, J = 3Hz), 7.29 (5H, s) Example 7, Sodium 9-0-(1 -ethoxy) prop-1 -ylclavu-lanate (e 18) A solution of benzyl 9-0-(1-ethoxy)prop-l-ylclavulanate (e 17) (572 mg) and sodium bicarbonate (128 mg) in tetrahydrofuran (22.5 ml) and water (7.5 ml), was hydrogenated over 10% palladium charcoal (250 mg) for 1 hour. The solution was filtered through Celite, (celite is a registered traig Itark) diluted with water and the tetrahydrofuran removed on a rotary evaporator. The aqueous solution was extracted with ethyl acetate and freeze dried to yield sodium 9-0-(1-ethoxy)· prop-l-ylclavulanate (e 18) (370 mg) . v max (KBr) 1785 and 1615 cm-1. fi(D20) 0.85 (3H, t, J = 7Hz), 1.16 (3H, t, J = 7Hz), 1.59 (2H, broad quintet J = 7Hz) , 3.05 (IH, d, J = 17Hz), 3.4 - 3.85 (4H, m), 4.19 (2H, d, J = 7Hz), 4.90 (IH, broad t, J = 7Hz), 4.93 (IH, s), .71 (IH, d, J = 3Hz). 6101 Example a.

Benzyl 9-0- (2-ethoxy) prop-2-ylclavulanate (e 19) To a stirred solution of benzyl clavulanate (e 1) (1 g) and ethyl isopropenyl ether (0.5 ml) in ethyl acetate (10 ml) was added p-toluenesulphonic acid (5 mg). The mixture was stirred at room temperature for 20 minutes and then passed through a short column of Kieselgel, eluting with ethyl acetate. The solvent was evaporated and the product isolated by column chromatography (Kieselgel 3:1 cyclohexane:ethyl acetate as eluent) to yield benzyl 9-0-(2-ethoxy)prop-2-ylclavulanate (e 19) (743 mg), v max (film) 1805, 1750 and 1700 cm1, δ (CDClj) 1.12 (3H, t, J = 7Hz), 1.31 (6H, s), 2.96 (IH, d, J = 17Hz), 3.37 (2H, q, J = 7Hz), 3.39 (IH, dd, J = 3 and 17Hz), 3.9 - 4.1 (2H, m), 4.73 (IH, broad t, J = 7Hz), 5.01 (IH, broad s), 5.13 (2H, s), 5.60 (IH, d, J = 3Hz), 7.26 (5H, s).

Example 9.

Benzyl 9-0-(1-ethoxy)cyclohexyl clavulanate (e20) To a stirred mixture of benzyl clavulanate (e 1) (578 mg) and ethyl cyclohexenyl ether (2 ml) was added mercuric trifluoroacetate {20 mg). The mixture was stirred at room temperature for 1.5 hours. Most of the solvent was removed on the rotary evaporator, and the product isolated by column chromatography of the residue (Kiesegel 4:1 cyclohexane:ethyl acetate) to yield (e 20) (767 mg). v max (film) 1805, 1750, 1700 cm-1, δ (CDC13) 1.14 (3H, t, J = 7Hz), 1.2 - 1.8 (10H, m), 2.96 (1H, d, J = 17Hz), 3.37 (2H, q, J = 7Hz), 3.43 (1H, dd, J = 3 and 17Hz), 3.9 - 4.15 (2H, m), 4.76 (1H, broad t, J = 7Hz), 5.04 (1H, s), 5.14 (2H, s), 5.60 (1H, d, J = 3Hz), 7.27 (5H, s).

Example 10. p-Methoxybenzyl 9-0-(2,3,4,6-tetra-O-acetyl-ci-D-gluco- A solution of p-methoxybenzyl clavulanate (elO) (S.38 g) in dry dimethylformamide (10 ml) was added dropwise over a few minutes to a stirred solution of a-acetobromoglucose (16.78 g) and collidine (5.3 ml) in dry dimethylformamide (50 ml) at 0°C under nitrogen. The reaction mixture was then stirred at room temperature overnight.

This was poured into ice-water (100 ml) which was extracted with ethyl acetate (3 x 100 ml). The organic extract was washed with dilute hydrochloric acid (5 M, 200 ml), dried with anhydrous sodium carbonate -magnesium sulphate, and evaporated to give an oil which was chromatographed over silica gel (100 g). Elution of the column with cyclohexane - ethyl acetate afforded the title compound (e22) (5.7 g) as an oil, [c]£ 45.8° (c. 1 .7, CHC13), vmax (CHClj) 1805, 1745, 1700, 1230, 1175, 1040 and 980 cm1. 6(CDCl3) 7.22 (2H, d, J = 9Hz, ArH), 6.83 (2H, d, J = 9Hz, ArH), 5.64 (IH, d, J = 4Hz, l'-GH), 5.61 (IH, d, J = 2.5Hz, -CH), 5.08 (2H, s, -CHjAr) , 3.76 (3H, s, -0¾) , 2.06 (9H, s, CH3CO2-), and 1.68 (3H, s, CH3CO2-) , m/e 649 (Μ*), 621, 607, 594, 549, 403, 331, 289, 288, 271, 259, 200 and 169 (Pound: C, 55.1; H, 5.4; N, 1.95%, requires C, 55.45; H, 5.45; N, 2.15%), followed by a mixture (7.8 g) of the title compound (e22) and a small amount of starting material.

Example ii. 610 1 Sodium 9-0-(2,3,4,6-tetra-0-acetyl-ct-D-glucopyranosyl) clavulanate OCOCH CH3C0l OCOCH (e22) _v CO2Na •ch2ococh3 (e23) A mixture of p-methoxybenzyl 9-0-(2,3,4,6-tetra-05 acetyl-a-D-glucopyranosyl)clavulanate (e22) (1.3 g) and sodium bicarbonate (0.168 g) in tetrahydrofuran water (5:1, 24 ml) was hydrogenated at room temperature and pressure in the presence of 10% palladium on charcoal (0.4 g) for 15 minutes. The mixture was filtered and the filtrate evaporated to give the title compound (e23) (0.96 g). [a]D +27.7° (c, 2.3, H2O), vmax (KBr) 1785, 1740, 1690, 1615 cm"1, δ(D20) 5.83 (IH, d, J = 5Hz, l'-CH), 5.75 (IH, d, J = 2.5Hz, 15 5-CH), 3.60 (IH, dd, J = 18Hz, J' = 2.5 Hz, 6a~CH), 3.07 (IH, d, J » 18Hz, 68-CH), 2.15 (9H, s, CH3CO2~), and 1.79 (3H, s, CH3CO2~). 4610*· Example 12. p-Msthoxybenzyl 9-0-(2,3,5-trl-0-benzyl-D-arablnofuranosyl) clavulanate (e24) To a solution of 2,3,5-tri-0-benzyl-g-D-arabino5 furanose (1.68 g), collidine (1.06 ml) and tetrabutylammonium bromide (1.29 g) in dry dichloromethane (5 ml) was added trifluoromethanesulphonic anhydride (1.13 g) at -7O°C, which reaction mixture was then stirred at roam temperature for 1 hour. A solution of _£-mstlicxyfcenzyl clavulanate (elO) (0.96 g) in dichloromethane (5 ml) was added to the reaction mixture which was then stirred at room temperature overnight. This was then washed with hydrochloric acid (5M, 10 ml) at 0°C, dried with anhydrous sodium carbonate magnesium sulphate and evaporated to give an oil which was chromatographed over silica gel (20 g). Elution of the column with cyclohexane - ethyl acetate gave the title compound (e24) (0.7 g). vmax (CHC13): 1805, 1745 and 1700 cm-1; 6{CDCl3): 7.20 (17H, s, ArH), 6.80 (2H, d, J = 9Hz, ArH), 20 5.51 (IH, d, J = 2.5Hz, 5-CH), 5.30 (IH, m, I'-CH), 5.05 (2H, s, CH2Ar), 4.98 (IH, m, 3-CH), 4.48 (6H, s, CH2Ar) 3.70 (3H, s, OCH3) and 2.90 (IH, d, J = 17Hz, 6g-CH). 6101 Example 3.3 Sodium 9-0-(1-butoxy)ethyl clavulanate A solution of 4-methoxybenzyl 9-0-(1-butoxy)ethyl clavulanate (ell) (800 mg) and sodium bicarbonate (160 mg) in aqueous tetrahydrofuran (5 ml water, 25 ml tetrahydrofuran) was hydrogenated for 20 minutes over 10% palladium on charcoal (400 mg). The solution was filtered and most of the tetrahydrofuran was removed under vacuum. The aqueous solution was extracted twice with ethyl acetate and freeze dried to give the title compound (e25) (447 mg). vmax (KBr disc): 1780, 1690, 1610 cm-1; (D2O)6: 0.84 (3H, triplet, J = 8Hz), 1.20 (3H, doublet, J = 5Hz), 1.15 - 1.65 (4H, multiplet), 3.01 (1H, doublet, 15 J » 18Hz), 3.45 - 3.7 (3H, multiplet), 4.15 (2H, doublet, J 53 8Hz), 4.65 - 4.95 (3H, multiplet), 5.68 (1H, doublet, J - 3Hz). 'Ί Example 14' 4-Msthoxybenzyl 9-0-(1-ethoxy)ethyl calvulanate CH.

H ch2-o-ch-o-ch2ch3 (elO) To a solution of jp-raethoxybenzyl clavulanate (elO) (1.5 g) and vinyl ethyl ether (1 ml) in ethyl acetate (15 ml) was added p-toluenesulphcnic acid (25 mg). The mixture was stirred for 15 minutes and then passed through a short column of KieselgelG, eluting with ethyl acetate.

The solvent was removed under vacuum and the product isolated by column chromatography (Kieselgel G, 3:1 cyclohexane: ethyl acetate as eluent) to yield (e26) (1.26 g). vmax (film): 1805, 1750, 1700 cm F (CDC13)6: 1.16 (3H, triplet, J= 8Hz) , 1.27 (3H, doublet, J = 5Hz), 2.97 (IH, doublet, J = 17Hz), 3.25 - 3.7 (3H, multiplet), 3.75 (3H, singlet), 4.0 - 4.15 (2H, multiplet), 4.5 - 4.85 (2H, multiplet), 5.0 (IH, singlet), 5.07 (2H, singlet), 5.60 (IH, doublet, J = 3Hz), 6.80 (2H, doublet, J = 9Hz), 7.21 (2H, doublet, J = 9Hz).

Exampleι5 clavulanate (e26) (1.185 g) and sodium bicarbonate (254 mg) in aqueous tetrahydrofuran (5 ml water, 25 ml tetrahydrofuran) was hydrogenated over 10% palladium charcoal (400 mg) for 25 minutes. The solution was filtered through Celite, and evaporated under vacuum, until most of the tetrahydrofuran had been removed.

The aqueous solution was extracted with three portions of ethyl acetate and freeze dried. The product was purified by column chromatography (Kieselgel G, 4:1:1 n-butanol:ethanol:water) and obtained by evaporation to yield the title compound (e27) (589 mg). vmax (KBr): 1795, 1695, 1615 cm-^.

(D2O)6: 1.23 (3H, triplet, J= 8Hz), 1.34 (3H, doublet, J = 6Hz), 3.11 (IH, doublet, J = 18Hz), 3.45 - 4.0 (3H, multiplet), 4.25 (2H, doublet, J = 8Hz), 4.75 - 5.1 (3H, multiplet), 5.77 (IH, doublet, J = 3Hz).

Example 16. 4610-1 Pharmacology: Using Conventional methods the following results were obtained: a. Compound of Examples 1.

MIC (pg/ml) of Ampicillin „ n Cone Inhibitor (pg/ml) Staph. Russell Kleb E 70 Proteus C 889 E. coli JT 39 E. coli JT 410 20 - 15.6 > 500 62.5 5 0.15 12.5 125 500 - 1 1.25 25 - - - 0 500 1000 > 2000 2000 62,5 6101 b. Compound of Example 13.

MIC (pg/ml) of Ampicillin Π Cone Staph. Kleb. 1 Proteus E. coii (pg/ml) Russell E 70 I C 889 JT 410 20 - - - 2000 1 K 5 (0.04) 1.6-3.1 J 15 > 2000 ’ 1 0.08 6-12 1 62.5 - 1 0 > 500 2000 | > 2000 62.5 Ϊ I

Claims (1)

1.CLAIMS: 1.A compound of the formula (I): Ρ η i 2 1 .CH 2 -O-CRR-XR {I) 'c° 2 h or a salt or ester thereof wherein X is an oxygen or sulphur atom; R 3- is a hydrogen atom or a lower alkyl group; R is a hydrogen atom or a lower alkyl group 1 3 which may if desired be joined to R and R is a lower alkyl group or an optionally inertly substituted lower alkyl group or is joined to R 3 to farm an optionally inertly 6. substituted heterocyclic ring of 5- cr 6- ring atoms, provided that R 1 and R 3 are not both hydrogen atom when R 3 is a lower alkyl group. A compound as claimed in claim 1 wherein X is an oxygen atom. A compound as claimed in claims 1 or 2 wherein R 1 is a hydrogen atom or a methyl or ethyl group. A compound as claimed in claims 1 or 2 wherein R 1 is a hydrogen atom. A compound as claimed in any of claims 1-4 wherein 2 R is a methyl or ethyl group. A compound as claimed in any of claims 1-4 wherein 2 R is a methyl group. 7. , A campourd as claimed in any of claims 1-6 wherein R is a methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tertbutyl group. 1/. 3. A compound as claimed in any of claims 1-6 wherein R is a methyl, ethyl, n-propyl or iso propyl group. 8. 9. A compound as claimed in any of claims 1-6 wherein R is a methyl group. 9. 10. A compound as claimed in any of claims 1-6 wherein R 3 is an ethyl group. 10. 11. A compound as claimed in any of claims 1-4 wherein 11. 12 3 the CR R XR moiety is a group of the sub-formula (a) -β u (b) wherein R is a group R or OR ,· R is a group R 4 c 4 4 0 4 or OR ; R is a group R or OR ; R is a group R 4 e 4 4 f 4 or OR ; R is a group R or OR ; R is a group R or R* or CH 2 R ' wherein R is a group of 1 - 4 carbon atoms, group of 1 - 4 carbon atoms. I 2 · A compound as claimed in claim ll wherein each of R a , r\ R°, R d , R e , r£ and R^ is independently a 12. 13. A compound as claimed in claim ll wherein R a , R^, R c , hydrogen atom or methyl group. id R d , R e , R f and R g all represent hydrogen atoms. (II) 13. 14. A compound of the formula (IX): CH 2 -O-CHR 2 -OR 3 'co 2 h 2 3 or a salt or ester thereof wherein R and R are as defined in any of claims 5 - 13. 2 3 14. 15. A compound as claimed in claim 14 wherein CHR OR is CH(CH 3 )OCH 3 . 2 3 15. 16. A compound as claimed in claim 14 wherein CHR OR is CH(CH 3 )OC 2 H 5 . 2 3 16. 17. A compound as claimed in claim 14 wherein CHR OR is ch(c 2 h 5 )oc 2 h 5 . A compou 2 3 17. 18. A compound as claimed in claim 14 wherein CHR OR is 2 3 18. 19. A compound as claimed in claim 14 wherein CHR OR is 19. 20- A compound as claimed in any of claims 1 - 19 in the form of the acid. 20. 21. A compound as claimed in any of claims 1 - 19 in the form of a salt. 4 6101 21. 22. A compound as claimed in any of claims 1-19 in the form of a lithium, sodium, potassium, calcium, magnesium, ammonium or substituted ammonium salt . 23. A compound as claimed in any of claims 1-19 in 5 the form of a lithium salt. 24. A compound as claimed in any of claims 1 - 19 in the form of a sodium salt. 25. A compound as claimed in any of claims 1 - 19 in the form of a potassium salt. 10 26. A compound as claimed in any of claims 1 19 which is an ester wherein the ester moiety is of the subformula (a) or (b): ''CO-A 1 (a) 'CO 2 CHA 2 A 3 (b) wherein A 1 is an alkyl group of 1-8 carbon atoms 15 optionally substituted by halogen or a group of the 4 4 4 4 4 formula 0A , OCOA , SA or S0 2 A wherein A is a hydrocarbon group of up to 6 carbon atoms; A is a hydrogen atom, an alkyl group of up to 4 carbon atoms or a phenyl group optionally substituted by halogen or 5 5 5 20 by a group A or OA where A is an alkyl group of up to 6 carbon atoms; and A is a phenyl group optionally c c substituted by halogen or by a group A or OA where A 3 is an alkyl group. 4610 1 22. 27. A compound as claimed in any of claims 1-19 which is a hydrolysable ester. 23. 28. A compound as claimed in any of claims 1 - 19 which is a hydrogenolysable ester. 24. 29. A compound as claimed in claim 27 wherein the ester is the methyl ester. 25. 30. A compound as claimed in claim 28 wherein the ester is the benzyl ester. 26. 31. A compound as claimed in claim 28 wherein the ester is a methoxybenzyl ester. 27. 32. A compound as claimed in claim 28 wherein the ester is a nitrobenzyl ester. 28. 33. A pharmaceutical composition which comprises a compound as claimed in any of claims 1-32 and a pharmaceutically acceptable carrier. 29. 34. A composition as claimed in claim 33 which comprises pharmaceutically acceptable salt of a compound as claimed in any of -claims 1-19. 30. 35. A composition as claimed in claim 34 wherein the salt is as claimed in claim 24. 31. 36. A composition as claimed in claim 34 wherein the salt is as claimed in claim 25. 32. 37. A composition as claimed in any of claims 33 - 36 in unit dosage form which contains from 20 to 250 mg of a compound as claimed in any of claims 1-32. 33. 38. A composition as claimed in any of claims 33-37 which also comprises a penicillin. 34. 39. A composition as claimed in any of claims 33-37 which also comprises a cephalosporin. 35. 40. A composition as claimed in claims 33 or 39 wherein the weight ratio of a compound as claimed in any of claims 1 - 32 to penciliin or cephalosporin is 1:10 to 10:1. 36. 41. A composition as claimed in claim 40 wherein the ratio is 2:1 to 1:5. 37. 42. A composition as claimed in claim 40 wherein the ratio is 1:1 to 1:3. 38. 43. A composition as claimed in any of claims 38 or 40 - 42 wherein the penicillin is ampicillin, amoxycillin or a pro-drug therefore. 39. 44. A composition as claimed in any of claims 38 or 40 - 42 wherein the penicillin is ampicillin trihydrate. 43. A composition as claimed in any of claims 38 or 40 - 42 wherein the penicillin is amoxycillin trihydrate. 40. 46. A process for the preparation of a compound of the formula (I) as defined in claim 1 or a salt or ester thereof which process comprises the reaction of an ester of clavulanic acid with a compound of the formula (V): Y-CR^-X-R 3 (V) 12 3 wherein X, R , R and R are as defined in claim 1 and Y is a readily displaceable atom or group,and thereafter, if desired, converting the thus produced ester into the free acid or salt or other ester thereof. 41. 47. A process as claimed in claim 46 wherein Y is X, Br, Cl, OSO 2 CH 3 or OSO 2 CgH 4 CH 3 · 42. 48. A process as claimed in claim 46 wherein Y is Br or Cl. 43. 49. A process as claimed in any of claims 46 - 48 wherein the etherification step is carried out in the presence of a base or low nucleophilicity. 44. 50- A process as claimed in any of claims 46 - 49 wherein the etherification step is carried out at -20°C to 30°C. 45. 51. A process as claimed in any of claims 46 - 50 adapted to the preparation of an ester. 46. 52. A process for the preparation of a compound of the formula (I) as defined in claim 1 wherein X is, an oxygen atcm and R E 2 is a hyirogen atom cr a salt ester thereof wherein R contains at least 2 carbon atoms and is optionally joined to R 3 which process comprises the reaction of an ester of clavulanic acid with a compound of the farnula (VI): r’V-CssCH - o - R 3 (VI) wherein R^R^CH is a group R 2 and R 3 is as defined in Claim 1; and thereafter, if desired, converting the thus produced ester into the free acid or a salt or other ester thereof. 4 6 1 0 i 47. 53 . A process as claimed in claim 52 wherein the etherification step is carried out in the presence of catalytic quantities of an acid. 48. 54. A process as claimed in claim 53 wherein the acid is HCl, POCl^, p-toluenesulphonic acid or BF^. 5 49. 55. -A process for the preparation of a compound of the formula (I) as defined in claim 1 wherein X is an ctygen atom ani R 1 is a hydrogen atom or a salt or ester thereof which precess comprises the reaction of an ester of clavulanic acid with a canpounl of the farnula (IX): 10 R 5 -0-CHR 2 -0R 3 (IX) wherein it, and are as defined in claim 1 and h j g a tertiary alkyl group of 4 - 6 carbon atoms; and thereaf ter, if desired, converting the thus formed ester into the free acid or a salt or other ester thereof. 15 50. 56. A process as claimed in claim 55 wherein Fr is a tert-butyl group. 51. 57. A process for the preparation of a compound of the formula (I) as defined in claim 1 or a salt thereof which process comprises the de-esterification of a corresponding ester of a compound of the formula (I). 52. 58. A process as claimed in claim 57 for the preparation of a salt of the compound of the formula (X) which process comprises the mild base hydrolysis of an ester of the compound of the formula (I). 5 53. 59. A process as claimed in claim 58 wherein the ester is the methyl ester. 54. 60. A process as claimed in claim 57 wherein the de-esterification is effected by hydrogenolysis. 55. 61. A process as claimed in claim 60 wherein the 10 hydrogenolysis is of a benzyl ester. 56. 62. A process as claimed in claim 60 wherein the hydrogenolysis is of a methoxybenzyl ester. 57. 63. A process as claimed in claim 60 wherein the hydrogenolysis is of a nitrobenz-yl ester. 15 58. 64. 4-Methcxybenzyl 9-0-&-butaxy)ethylclavulanate. 59. 65. Benzyl 9-O-tetrahydropycan-2-ylclavulanate. 60. 66. Lithium 9-O~tetrahydropyran-2-ylclavulanate. 61. 67. 4-tfcthaxybenzyl 9-O-tetrahydrafuran-2-ylclavulanate. 62. 68. Sodium 9-O-teteahydrOfuran-2-ylclavulanate.