GB1572993A - Ester derivatives of cefuroxime - Google Patents

Description

(54) ESTER DERIVATIVES OF CEFUROXIME (71) We, GLAXO OPERATIONS UK LIMITED, formerly known as GLAXO LABORATORIES LIMITED. a British Company of Greenford, Middlesex do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed. to be particularly described in and by the following statement: This invention is concerned with improvements in or relating to cephalosporin antibiotics. More particularly the invention is concerned with biologically acceptable ester derivatives of (6R 7R )-3-carbamoyloxymethyl-7-[ (Z)-2-(fur-2-yl)-2-methoxyimino- acetamido]ceph-3-em-4-carboxvlic acid (i.e. the syn isomer), which has the approved name "cefuroxime''.

Cefuroxime, as disclosed in British Patent Specification No 1453049 is a valuable broad spectrum antibiotic characterised by high activity against a wide range of gram-positive and gram-negative miroorganisms. this property being enhanced by the very high stability of the compound to ss-lactamases produced by a range of gram-negative microorganisms.

Additionally the compound is stable in the body owing to its resistance to the action of mammalian esterases, and gives high serum levels following parenteral administration (e.g.

in the form of the sodium salt) to human and animal subjects, while exhibiting low serum binding.

Cefuroxime and its salts, for example alkali metal salts such as the sodium salt, are principally of value as injectable antibiotics since they are poorly absorbed from the gastro-intestinal tract and are therefore present in sera and urine onlv in low concentrations after oral administration. We have accordingly conducted extensive studies into the possible activity upon oral administration of various derivatives of cefuroxime, since the development of derivatives which are absorbed through the gastro-intestinal tract and exhibit good antibacterial activity following oral administration would extend still further the valuable therapeutic potential of cefuroxime.

It is known from the literature pertaining to lS-lactam antibiotics that the effect upon oral administration of penicillin antibiotics such as ampicillin can be improved by converting the carboxy group at the 3-position of the penam nucleus to certain esterified carboxy groups; there have also been some proposals that the activity upon oral administration of certain cephalosporin antibiotics may be enhanced bv esterification in similar manner. It is believed that the presence of an appropriate esterifying group enhances absorption of the compound from the gastro-intestinal tract, whereupon the esterifying group is hydrolysed by enzymes present in, for example, serum and bodv tissues to yield the antibiotically active parent acid.It will be appreciated that the precise nature of the esterifying group is critical since it is necessarv that the ester should be sufficientlv stable to allow the ester to reach the site of absorption without undergoing significant degradation. e.g. in the stomach, while on the other hand the ester must be sufficientlv susceptible to esterase hydrolysis so that the antibioticallv active parent acid is liberated within a short time of the ester being absorbed.

The selection of a particular esterifying group to enhance the effect upon oral administration of a t3-lactam antibiotic will also be influenced by the specific 13-lactam compound chosen. Thus, for example, esterifying groups which have been found effective in improving the activity of orallv administered penicillin antibiotics do not necessarily convey similar advantages to antibiotics of the cephalosporin series. An example which may be cited here is the cise of pivaloyloxymethyl esters. Thus, the pivaloyloxymethyl ester of, for example, ampicillin is known to improve the oral absorption of ampicillin.The pivaloyloxymethyl ester of cefuroxime on the other hand, exhibits little effect upon oral administration, possibly because the ester is not sufficiently absorbed from the gastrointestinal tract or alternatively is substantially resistant to esterase hydrolysis so that the antibiotically active acid is not liberated to any significant extent following absorption We have now found that esters of cefuroxime, which may be represented by the formula

(where R is a primary or secondary alkyl group containing 1 to 4 carbon atoms), possess properties which render these compounds of significant potential value as orally administrable antibiotics. When the group R possesses an asymetric carbon atom. the individual diastereoisomers of formula I as well as mixtures thereof, are embraced by the invention.

The reference herein to the primary or secondary alkyl group denotes an alkyl group in which the carbon atom of attachment is bonded to at least one hydrogen atom.

Thus the esters (I) possess reasonable stabilitv as evidenced by the fact that they exhibit low antibacterial activitv in vitro compared to cefuroxime (this indicates that a high proportion of ester remains unchanged throughout the in vitro tests and so confirms the stability of the esters). The esters are, on the other hand, extremely susceptible to esterase hydrolysis leading to formation of cefuroxime, as evidenced by in vitro tests emploving esterases derived from rat liver, human liver and human serum.

In i'iio testing in mice. rats and dogs confirms that oral administration of esters of (I) leads to significantly greater absorption of cefuroxime. as evidenced by higher serum levels and increased urinary recovery. than does oral administration of cefuroxime itself.

Of the compounds of formula I the following have been shown to provide particularly good absorption of cefuroxime:- acetoxymethyl (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2- (fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate; propionvloxymethyl (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em4-carboxylate: isobutyryloxymethyl (6R, 7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2methoxyiminoacetamido]ceph-3-em-4-carboxylate; and isovaleryloxymethyl (6R,7R)-3carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4- carboxylate.

The compounds (I) may be prepared in conventional manner, for example by reacting cefuroxime or a salt thereof (e.g. an alkali metal salt such as the sodium or potassium salt or an onium salt, e.g. an ammonium for example a quaternary ammonium salt) with a haloester of formula X. CH2. O. CO. R (II) (where R is as defined above and X is halogen such as chlorine, bromine or iodine).The reaction is conveniently effected in solution in an inert organic solvent (e.g. an N.N-disubstituted amide such as N,N-dimethyl-formamide or N,N-dimethylacetamide . a ketone such as acetone, a sulphoxide such as dimethylsulphoxide. a nitrile such as acetonitrile. or hexamethyl phosphoric triamide) at a temperature in the range -50" to +l5CC, e.g. -1(js to +5() C. conveniently between () C and room temperature. When a cefuroxime salt. for example, the potassium salt. is employed as starting material and the reaction is effected in a nitrile solvent, a crown ether such as 18-crown-6 mav. if desired, be emploved. When cefuroxime acid is employed as starting material it may be advantageous to effect the reaction in the presence of a base. e.g. a weak inorganic base such as sodium carbonate or potassium carbonate, it is convenient to add the base to the cefuroximecontaining reaction system prior to addition of the holoester (II). The use of potassium carbonate as base in conjunction with a compound (II) in which X is bromine or iodine has been found advantageous in that under these conditions the formation of a ceph-2-em ester product is minimised. It is convenient to employ substantially equivalent amounts of cefuroxime and base, e.g. about 0.5 moles of a diacidic base such as potassium carbonate per mole of cefuroxime. The haloester (II) is conveniently employed in slight excess, e.g. in an amount of 1-1.5 moles per mole of cefuroxime.

The course of the reaction may readily be monitored by t.l.c., since the process involves conversion of a polar acid or salt starting material to a neutral ester product.

The esters (I) may also be prepared by acylation of a compound of formula

(wherein R is as hereinbefore defined) or an acid addition salt or N-silyl derivative thereof, using (Z)-2-(fur-2-yl)-2-methoxyiminoacetic acid or a reactive derivative thereof, for example in the manner disclosed in the aforementioned British Patent Specification No.

1453049.

Compounds of formula I may conveniently be prepared by acylating a compound of formula (Ill) with an acylating agent comprising an acid halide, particularly an acid chloride or bromide, of the said acid. Such acylation may be effected at temperatures of from -50 to +50"C, preferably -20 to +30"C. The acylation may be effected in aqueous or non-aqueous media.

Acylation with an acid halide may be effected in the presence of an acid binding agent (e.g. a tertiary amine such as triethylamine or dimethylaniline. an inorganic base such as calcium carbonate or sodium bicarbonate, or an oxirane, preferably a 1,2-(C2-6) alkylene oxide such as ethylene oxide or propylene oxide) which serves to bind hydrogen halide liberated in the acylation reaction.

The free acid may itself be used as the acylating agent. Such acylations are desirably conducted in the presence of. for example, a carbodiimide such as N,N'dicyclohexylcarbodiimide, a carbonyl compound such as carbonyldiimidazole: or an isoxazolinium salt such as N-ethyl-5-phenylisoxazolinium-3'-sulphonate or N-t-butyl-5methylisoxazolinium perchlorate. The condensation reaction is desirably effected in an anhydrous reaction medium, e.g. methylene chloride, dimethylformamide or acetonitrile.

Acvlation may also be effected with other amide-forming derivatives of the free acid such as, for example, a symmetrical anhvdride or a mixed anhydride, e.g. with pivalic acid or formed with a haloformate such as a C1-6 alkyl haloformate. The mixed or symmetrical anhydrides may be generated in sits. Thus, for example, a mixed anhydride may be generated using N-ethoxycarbonvl-2-ethoxy- 1 2-dihydroquinoline. Mixed anhydrides may also be formed with phosphorus acids (for example phosphoric or phosphorous acids), sulphuric acid or aliphatic or aromatic sulphonic acids (for example p-toluenesulphonic acid).

The above described starting materials of formula (Ill) may be prepared in a conventional manner, for example. using the techniques described in U.S. Patent Specification No. 3,905,963 and British Patent Specifications Nos. 1,041,985 and 1.350,772.

If the desired ester product is significantly contaminated by the corresponding ceph-2-em isomer the product may be oxidised (e.g. by treatment with a peracid such as metaperiodic acid, peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid or with t-butyl hypochlorite in the presence of a weak base such as pyridine) to give the ceph-3-em 1-oxide ester, which may then be reduced (e.g. by treatment with acetyl chloride and potassium iodide) to yield substantially pure ceph-3-em ester.

It may be desirable to purify the haloester (II) before use, e.g. by distillation or selective hydrolysis. to remove impurities such as compounds of formula X.CHI.O 0. CH2 . X (IV) (where X is as defined above).

The esters of formula I may be formulated as compositions for oral administration in ( onventional manner, with the aid of any necessary pharmaceutical carriers or excipients.

The compositions are conveniently prepared as tablets. capsules or sachets, advantageously in unit dose form, and may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants and wetting agents. Tablets may be coated in conventional manner. The active compounds may further be formulated in rectal compositions such as suppositories or retention enemas.

The composltlons may contain from 0.1% upwards. e.g. 0.1-99% conveniently from 10-60% of the active ingredient (I), depending on the method of administration.

Compositions in dosage unit form conveniently contain 50-500 mg of the active ingredient (calculated as cefuroxime). Doses employed for adult human treatment will typically be in the range 500-5000mg per day, e.g. 1500mg per day, (calculated as cefuroxime), although the precise dose will depend on, inter alia, the frequency of administration.

The following examples illustrate the invention. All temperatures are in C. The potassium carbonate employed was dried at 1200 in vacuo and finely ground. The N,N-dimethylformamide employed was dried by passage through acidic alumina. In Examples 4 and 5 the melting points were determined by the capillary method and are uncorrected.

EXAMPLE 1 Acetoxymethyl (6R, 7R)-3-carbamoyloxymethyl-7[(z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate A solution of (6R.7R)-3-carbamoyloxymethyl-7[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (12.00 g) in N.N-dimethylformamide (70 ml) was stirred for 10 minutes with potassium carbonate (1.95 g). during which time the mixture became darker and the solid almost completely dissolved. A solution of acetoxymethyl bromide (5.0 g) in N.N-dimethylformamide (15 ml) was then added, whereupon precipitation of potassium bromide occurred almost immediately.The reaction mixture was stirred at 21 for 30 minutes, after which it was shown by t.l.c. (developing wiht chloroform:acetone = 2:1 and observing the spots under u.v. light and by spraying with ninhvdrin and heating to 1200) to contain no unreacted cephalosporin starting material. The reaction mixture was then poured into a mixture of 2N-hydrochloric acid (350 ml) and ethyl acetate (350 ml), and the aqueous phase was extracted with further ethyl acetate (2x200 ml).The organic extracts were combined and were washed successively with 2Nhydrochloric acid (2x300 ml). water (2x300 ml), aqueous sodium bicarbonate solution (3%, 300 ml). water (3x300 ml), and saturated sodium chloride solution (2x300 ml), and dried (Mg SO4), and the solvent was removed in vacuo to give a yellow foth (13.87 g). This product was absorbed onto a column of silica gel (Hopkin and Williams. 100 to 200 mesh-330g) which was eluted with chloroform:acetone = 2:1; 25 ml fractions were collected, Evaporation of fractions 11 to 32 gave crude title ester. which crystallised during the evaporation.The resulting solid (7.217 g) was triturated with diethylether to give the title ester (6.58 g) as a white powder. m.p. 181 to 183 (Kofler): [α]D + 58 (c 0.98. DMSO).

[α]D + 72 (c 1.32. dioxan): #max (EtOH) 276 nm (# 19.750). The nmr and infrared data are shown in Table 1 hereinafter. The structure of the product was also confirmed by microanalysis.

EXAMPLE 2 Propionyloxymethyl (6R, 7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2methoxyiminoacetamido]ceph-3-em-4-carboxylare (a) Potasslum carbonate (690mg) was stirred for 30 minutes with a soluion of (6R.7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em4-carboxylic acid (4.24g) in N.N-dimethylformamide (25ml). A solution of chloromehtyl proplonate (1.226g) in N.N-dimethylformamide (1m1) was added to the resulting dark brown solution and the reaction mixture was stirred for 20 hours and poured into 2N-hydrochloric acid (200ml) to give a brown solid which dissolved on addition of ethyl acetate (200ml).The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution (200 ml), dried (Mg SO4) and evaporated to a brown foam. which on trituration with di-isopropyl ether (75 ml) afforded a brown solid which was filtered off.

washed with more di-isopropyl ether and dried to give the title ester contaminated with ca.

55 @ of the corresponding ceph-2-em-isomer (by n.m.r. estimation), as a pale brown powder (3.915 g).

(b) A solution of m-chloroperbenzoic acid (1.424g) in dichloromethane (20ml) was added to a solution of the product from (a) above (3.82g) in dichloromethane (100ml) at ca. 0 .

immediately causing the separation of a brown gel. After 10 minutes the mixture was allowed to warm up to room temperature and after a further 20 minutes the mixture was evaporated in vacuo. The resulting yellow solid was triturated with diethylether. filtered and washed with ether to give propionyloxymethyl (1R and 1S. 6R. 7R)-3carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4 carboxylate, 1-oxides as a pale powder (3.696g), m.p. 175-177 (decomp.); [ainit) + 80 (c 0.5, DMSO). The structure of this product was confirmed by i.r. and n.m.r. spectroscopy and bv microanalysis.

(c) A solution of the product from (b) above (3.592g) in N.N-dimethylformamide (15 ml) was treated with potassium iodide (4.53g) and the mixture was cooled to -10 , whereupon acetyl chloride (1.02 ml) was added. The ensuing reaction appeared to be complete after 30 minutes (by t.l.c.), and the reaction mixture was then added dropwise into aqueous sodium metabisulphite solution (3% w/v, 300ml) to yield a precipitate which was filtered off and dissolved in ethyl acetate (100 ml). The organic solution was washed successively with 2N-hydrochloric acid (100ml) and saturated aqueous sodium bicarbonate (100ml) and was then dried (Mg SO4) and evaporated in vauco to give a cream solid.This product was subjected to column chromatography on Kieselgel 60 silica (100g), elution being carried out with chloroform: acetone (12:1). Appropriate fractions were combined and evaporated in vacuo to afford a pale yellow foam (2.226g) which was triturated with di-isopropyl ether, filtered and dried to give the title compound (2.108g) as a very pale yellow powder, m.p.

94-103 ; [α]D20 + 36 9c 1, DMSO); #max (EtOH) 277 nm (# 17,660). The n.m.r. and infrared data are shown in Table 1 hereinafter. The n.m.r. spectrum indicated that some ceph-2-em isomer was still present. The structure of the product was also confirmed by microanalysis.

EXAMPLE 3 Propionyloxymethyl (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate A solution of chloromethyl propionate (4.88g. 40mmole) in acetone (10ml) was added to a solution of sodium iodide (18g. 120mmole) in acetone (70ml): cloudiness instantly resulted. The reaction mixture was refluxed (30 minutes) and then evaporated in vacuo to give a dark solid.

This solid was partially dissolved in purified N,N-dimethylformamide (Süml). and the resultant mixture was treated with a solution of potassium (6R,7R)-3-carbamoyloxymethyl7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (9.24g 20 mmole) in purified N.N-dimethylformamide (50ml).

T.l.c. after ca 10 minutes indicated absence of cephalosporin starting material so after 20 minutes the reaction mixture was poured into 2N hydrochloric acid (I litre) to give a brown precipitate which dissolved on addition of ethyl acetate (500ml). The dark organic layer was separated and washed successivelv with saturated aqueous sodium bicarbonate solution (500ml) and sodium metabisulphite solution (500ml) (this gave a pale yellow organic layer) and evaporated in vacuo to give a viscous brown oil which crystallfsed to a pale yellow solid.

Trituration of this solid with di-isopropyl ether (150ml) gave a pale solid which was filtered off and washed with fresh di-isopropyl ether and dried in vacuo to give the title ester (7.00g) as a white powder m.p. 170 to 174 (dec) [α]D + 49 (c 1.0, DMSO), mux (EtOH) 276nm (E1cm1 378, # 19.300), [Found: C. 47.4: h. 4.5; N, 10.7: S. 6.4: C30H22N4O10S (510.48) requires C. 47.05: H. 4.3; N. 11.0: S. 6.3%].

The n.m.r. and infrared data are shown in Table 1 hereinafter.

Preparation of starting materials: Prepararlon I Chloromethyl Isobutvrate 2-Methylpropanoyl chloride (10.2g) was added to paraformaldehyde (1.86g. 56mmolde) containing a little zinc chloride and the mixture was heated to reflux for 40 minutes. During this time the paraformaldehyde dissolved and the mixture turned brown. The supernatant liquid was decanted from the zinc chloride and distillation afforded the title ester (3.45g) b.p. 45 to 56 /40mm which was characterised by its nmr (CDCI3) and infrared (CHBr3) spectra.

Preparation 2 Bromomerhyl 3-methylbutanoate 3-Methylbutanoyl bromide (3.48g. 21 mmole) was added to paraformaldehyde (630mg, 21 mmole) and the mixture was refluxed for 15 minutes during which time the paraformaldehyde dissolved. The resulant pale brown liquid was distilled under reduced pressure to give the title ester (1,89g) as a colourless liquid, b.p 80 to 82 /37mm, which was characterised by its nmr ) cdcl3) and infrared (CHBr3), spectra.

EXAMPLE 4 Isoburyryloxymethyl (6R, 7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2methoxyiminoacetamido]-ceph-3-em-4-carbaxylate Chloromethyl isobutyrate (2.04g, 15mmole) in acetone (45 ml) was mixed with sodium iodide (6.75g, 45mmole) and the mixture refluxed for 30 minutes. Evaporation in vacuo gave the iodomethyl ester (3.95g) as a dark red oil. (6R,7R)-3-Carbamoyloxymethyl-7 (Z)-2-(fur-2-yl )-2-methoxyiminoacetamidojceph-3-em-4-carboxylic acid, potassium salt (5.52 g, 12 mmole) was added to a solution of the above iodomethyl ester (3.9 g) in pure N,N-dimethylformamide (35 ml) producing a dark solution.After 20 minutes the reaction mixture was poured into 2N hydrochloric acid (350 ml) to give a yellow solid which dissolved on addition of ethyl acetate (350ml). The organic phase was separated and washed with saturated sodium bicarbonate solution (350 ml), sodium metabisulphite solution (350 ml! and brine (200 ml), dried over magnesium sulphate and evaporated in vacuo to give a yellow foam. The foam was triturated with di-isopropyl ether (50 ml).

filtered and washed with fresh di-isopropyl ether and dried to give the title compound (5.344 g,) as a yellow powder, m.p. 67 to 74 ; [α]D22 + 37 (c 1.0, DMSO); #max (EtOH) 277 nm (E1em1 362: E 18,985); Jfound:- C.47.9: H,4.9; N,10.15; S,6.0; C21H24N4O10S (524.5) requires C.48.1: H,4.6: N.10.7: S.6.1%].

The nmr and infrared data are shown in Table 1 hereinafter.

EXAMPLE 5 Isovaleryloxymethyl (6R, 7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2methoxyiminoacetamido]ceph-3-em-4-carboxylate Bromomethyl 3-methylbutanoate (1.328 g. 6.7 mmole) was added to a solution of (6R,7R )-3-carbamovloxvmethvl-7-( (Z)-2-(fur-2-yl )-2-methoxyiminoacetamido]ceph-3-em- 4-carboxvlic acid. potassium salt (7.772g. 6mmole) in purified N,N dimethylformamide (18 ml). The mixture was allowed to react for 15 minutes and was then worked up as described in Example 4 to give the slightly impure title compound (2.809 g).

A portion ('.75g) of the title compound was subjected to column chromatography (on Kieselgel 60.60g): elution was with chloroform:acetone (7:1). The desired fractions were combined and evaporated in vacuo to yield a pale yellow foam which, on trituration was di-isopropvl ether, afforded a white solid which was filtered and washed with fresh di-isopropvl ether and dried in vacuo to give the pure title compound (2.095 g) as a white powder m.p. 66 to 73": [α]D21 +74.5 )c 1.0. DMSO); #max (EtOH) 277.5 nm (Elcm 348: E 18.740): [Found: C,47.7: H.4.9: N.10.0: S.5.8; C22H26N4O10S (538.5) requires C.49.05: H.4.9: N.10.4; S.5.95%]. The nmr and infrared data are shown in Table 1 hereinafter.

TABLE I Physical Properties of the products of Example 1-5

Exam- Solvent r (100 MHz; 3Hz) ple re 5: No for v T L: 6.27 5.10 0 i 4.11 v 6.09 0.20 4.16 4.74 6.48 5.39 3.36 = x v v 3.29(m) (d9) V d(5) (318) (313) -CH2OCCH3 V 7.90 (s) o=v O=V ovv o=vsU o=v o o - o o o rt (s) 5.12 obscured 0 0 2 DMSO-d6 3.2 to 6.10 0.24 4.08 4.75 6.40 5.40 by a2 j 7.54 (q7) d V . ~ V (dd) (d5) (314) and Q, -C H2OCCH2CH3 k V . ~ V . ~ i j k a 3 DMSO-d6 rl 0.24 4.15 4.77 6.48 5.44 3.40 m9 j 7.60 (q8) 3.35 (m) < } (m) (d5) (318) (313) -CH2OCCH2CH3 n 8.96 n j k ~ ~ 4.13 6.38 ~ ~ 4 Ir;v;2 3.2 to 6.10 0.21 (dd 4.74 (s) v;v;;Z In'vi3 ~ ~ (d9) (9,5) (d5) (312) -CHOCCH j 7.38(m) my CH3k 2.10 6.24 5.07 0 CHi 4.05 5 DMSO6) 3.2 to 6.07 0.16 4.()8 4.70 6.46 5.35 3.36 II 413J=6 9-cl: '"^ (d9) (dd (d5) (318) (312) -CH2OCCH2 CR j 7.70(d7) 9,5) i j k k 7.96(m) CH3l t 9.05(d7) E E O E O O = s O O O O " a m a a a a av l > e X O TABLE 1 (Continued) Vmax (cm-1) Example No Solvent NH2and NH ss-lactam CO2R OCONH2 CONH 1 Nujol 3452 1780 1730 1708 1660 3420 1528 2 CHBr3 3565 1756 1692 3440 1786 1740 obscured 1520 3 CHBr3 3500 1745 1680 3390 1785 1730 obscured 1530 4 CHBr3 351() 1740 1720 1680 3390 1778 1730 1576 1512 5 CHAR, 3530 1754 1730 1684 3400 1784 1730 1582 1520 EXAMPLE A Tablet Composition:: Acetoxymethyl (6R. 7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (micronised) 292.5 mg Sodium starch glycolate (Primojel) 7.0 mg Microcrystalline cellulose (Avicel PH 101) 48.75 mg Magnesium stearate 1.75 mg Total weight: 350.0 mg The word "Avicel" is a registered Trade Mark Method of preparation The magnesium stearate was blended with the active ingredient and tablet slugs were prepared by direct compression. The slugs were broken down through 12 mesh. 16 mesh and 20 mesh consecutively and the granules were blended with the sodium starch glycolate and microcrystalline cellulose. The blend was compressed on 10.5 mm diameter normal concave punches to a tablet weight of 350 mg.The tablets may be film coated by the aqueous or organic solvent method using cellulose derivatives with plasticiser and colouring matter.

As an alternative to the preliminary slugging stage the active ingredient may be densified by roller compaction.

EXAMPLE B Powder for oral suspension (in sachet) Composition (per sachet).

Acetoxymethyl (6R, 7R )-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl )-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (milled) 292.5 mg Sodium carboxymethyl cellulose (low viscositv) 90 mg Sunset yellow FCF 5 mg Spray-dried orange flavour 150 mg Caster sugar 2.2 g Method of preparation The active ingredient was milled (using a fluid energy mill) and blended intimatelv with the sodium carboxymethvl cellulose. the flavour ingredient and the colouring agent. This blend was then further blended with the caster sugar, adding the latter in two stages. The required weight was transferred to a paper/aluminium/polythene sachet and sealed by heat.

The contents of each sachet were intended for constitution in about 15 mls of water, shortly before administration.

WHAT WE CLAIM IS: 1. Compounds of the formula

(where R is a primary or secondary alkyl group containing 1 to 4 carbon atoms).

2. A compound as claimed in claim 1 wherein R is a primary or secondary alkyl group containing 3 or 4 carbon atoms.

3. Acetoxymethyl (6Rs7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy- imino-acetamido]ceph-3-em-4-carboxylate.

4. Propionyloxymethyl (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy- iminoacetamido]ceph-3-em-4-carboxylate.

5. Isobutyryloxymethyl (6R.7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy- iminoacetamido]ceph-3-em-4-carboxylate 6. Isovaleryloxv (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyimino- acetamido]ceph-3-em-4-carboxylate.

7. A process for the preparation of a compound of formula I (as defined in claim 1) which comprises either (A) reacting (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2- methoxviminoacetamidojceph-3-em-4-carboxylic acid (i.e. cefuroxime) or a salt thereof with a haloester of formula X.CH2 .O. CO . R (Il) (where R is as defined in claim 1 and X is halogen) or (B) acylating a compound of formula

(where R is as defined in claim 1) or an acid addition salt or N-silyl derivative thereof, with (Z)-'-(fur-'-vl)-2-methoxyiminoacetic acid or a reactive derivative thereof.

8. A process as claimed in claim 7 wherein cefuroxime or a salt thereof is reacted with a haloester of formula (II) in which X is chlorine, bromine or iodine.

9. A process as claimed in claim 7 or claim 8 wherein an alkali metal or onium salt of cefuroxime is reacted with the said haloester of formula (I1) 11). A process as claimed in claim 7 or claim 8 wherein cefuroxime is reacted with the said haloester of formula (II) in the presence of a base.

11. A process as claimed in claim 7 substantially as herein described.

12. A process for the preparation of compounds of formula I (as defined in claim 1) substantially as herein described in any of Examples 1 to 5.

13. Compounds of formula I (as defined in claim 1) whenever prepared by a process as claimed in any of claims 7 to 12.

14. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 6 and 13 in association with at least one pharmaceutical carrier or excipient.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (1)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   The contents of each sachet were intended for constitution in about 15 mls of water, shortly before administration.

   WHAT WE CLAIM IS:

   1. Compounds of the formula

   (where R is a primary or secondary alkyl group containing 1 to 4 carbon atoms).

   2. A compound as claimed in claim 1 wherein R is a primary or secondary alkyl group containing 3 or 4 carbon atoms.

   3. Acetoxymethyl (6Rs7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy- imino-acetamido]ceph-3-em-4-carboxylate.

   4. Propionyloxymethyl (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy- iminoacetamido]ceph-3-em-4-carboxylate.

   5. Isobutyryloxymethyl (6R.7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy- iminoacetamido]ceph-3-em-4-carboxylate

   6. Isovaleryloxv (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyimino- acetamido]ceph-3-em-4-carboxylate.

   7. A process for the preparation of a compound of formula I (as defined in claim 1) which comprises either (A) reacting (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2- methoxviminoacetamidojceph-3-em-4-carboxylic acid (i.e. cefuroxime) or a salt thereof with a haloester of formula X.CH2 .O. CO . R (Il) (where R is as defined in claim 1 and X is halogen) or (B) acylating a compound of formula

   (where R is as defined in claim 1) or an acid addition salt or N-silyl derivative thereof, with (Z)-'-(fur-'-vl)-2-methoxyiminoacetic acid or a reactive derivative thereof.

   8. A process as claimed in claim 7 wherein cefuroxime or a salt thereof is reacted with a haloester of formula (II) in which X is chlorine, bromine or iodine.

   9. A process as claimed in claim 7 or claim 8 wherein an alkali metal or onium salt of cefuroxime is reacted with the said haloester of formula (I1) 11). A process as claimed in claim 7 or claim 8 wherein cefuroxime is reacted with the said haloester of formula (II) in the presence of a base.

   11. A process as claimed in claim 7 substantially as herein described.

   12. A process for the preparation of compounds of formula I (as defined in claim 1) substantially as herein described in any of Examples 1 to 5.

   13. Compounds of formula I (as defined in claim 1) whenever prepared by a process as claimed in any of claims 7 to 12.

   14. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 6 and 13 in association with at least one pharmaceutical carrier or excipient.