GB2029823A - Cephalosporin Antibiotics - Google Patents

Abstract

Antibiotic compounds of the general formula <IMAGE> [wherein R<1> is a furyl or thienyl group; R is a methyl, amino, methylamino or 2-chloroethyl amino group; and Z is a tetrazol-5-yl group] and non-toxic salts and physiologically acceptable equivalents thereof exhibit broad spectrum antibiotic activity characterised by particularly high activity against gram-negative microorganisms, and very high stability to beta -lactamases produced by a range of such microorganisms. Particularly preferred compounds of the invention include (6R, 7R)-3- acetoxymethyl-7-[Z-2-(fur-2-yl)-2- (tetrazol-5-ylmethoxyimino) acetamido] ceph-3-em-4-carboxylic acid and (6R, 7R)-3-carbamoyloxymethyl-7-[Z-2- (fur-2-yl)-2-(tetrazol-5-yl methoxyimino) acetamido] ceph-3- em-4-carboxylic acid, these compounds being useable, inter alia, as their sodium salts.

Description

SPECIFICATION Improvements in or Relating to Cephalosporin Antibiotics This invention is concerned with improvements in or relating to cephalosporin compounds, and is more particularly concerned with a novel class of cephalosporin compounds possessing valuable antibiotic properties.

The cephalosporin compounds in this specification are named with reference to "cepham" after J. Amer. Chem. Soc., 1962, 84, 3400, the term "cephem" referring to the basic cepham structure with one double bond.

Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in human beings and animals, for example in the treatment of diseases caused by bacteria which are resistant to other antibiotics such as penicillin compounds, and in the treatment of penicillin-sensitive patients. In many instances it is desirable to employ a cephalosporin antibiotic which exhibits acitivity against both gram-positive and gram-negative microorganisms, and a significant amount of research has been directed to the development of various types of broad spectrum cephalosporin antibiotics.

Considerable interest is currently being directed to the development of broad spectrum cephalosporin antibiotics which possess high activity against gram-negative organisms.

Commercially available cephalosporin antibiotics such as cephalothin and cephaloridine tend to exhibit comparatively low activity against certain gram-negative organisms such as Proteus organisms, which are an increasingly common source of infection in humans. It is well known that cephalosporin antibiotics normally exhibit low toxicity in man, so that the development of broad spectrum cephalosporin antibiotics possessing high activity against gram-negative organisms such as strains of Proteus fulfils a significant need in chemotherapy.

The present invention provides compounds of the general formula

[wherein R' is a furyl (2- or 3-) or thienyl (2- or 3-) group; R is a methyl, amino, methylamino or 2chloroethyl-amino group; and Z is a tetrazol-5-yl group] and non-toxic salts and physiologically acceptable equivalents thereof, the compounds being syn isomers or existing as mixtures of syn and anti isomers containing at least 75% of the syn isomer.

The tetrazol - 5 - yl group Z in the above general formula may exist in the tautomeric forms

Both such forms are included within the scope of the invention.

These compounds exhibit broad spectrum antibiotic activity characterised by particularly high activity against gram-negative microorganisms, including those which produce p-lactamases, and also possess very high stability to p-lactamases produced by a range of gramnegative organisms. A characteristic feature of the compounds is their high in vitro activity against gram-negative organisms such as Enterobacter cloacae, Serratia marcescens and Klebsiella aerogenes. The compounds have particularly high activity against strains of Escherichia coli, Haemophilus influenzae and Proteus organisms, e.g. strains of Proteus organic and Proteus mirabilis.

The compounds of the invention are defined as having the syn isomeric form as regards the configuration of the group --OCH,Z with respect to the carboxamido group. In this specification the syn configuration is denoted structurally as

The compounds may exist as mixtures of syn and anti isomers provided that such mixtures contain at least 75% (advantageously at least 90%) of the syn isomer. We prefer, however, the compounds to be syn isomers essentially free from the corresponding anti isomer.

Non-toxic salt derivatives which may be formed from the compounds of general formula (I) include inorganic base salts such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts); organic base salts (e.g. procaine, phenyl ethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine and N-methylglucosamine salts); amino acid salts (e.g. lysine, arginine, ornithine, and histidine in the d-, I- and di forms). The salts may also be in the form of resinates formed with, for example, a polystyrene resin or cross-linked polystyrenedivinylbenzene copolymer resin containing amino or quaternary amino groups.

Use of highly soluble base salts (e.g. alkali metal salts such as the sodium salt) of compounds of formula (l) is generally advantageous in therapeutic applications because of the rapid distribution of such salts in the body upon administration. Where, however, insoluble salts of compounds (I) are desired in a particular application, e.g. for use in depot preparations, such salts may be formed in conventional manner, for example with appropriate organic amines.

The expression "physiologically acceptable equivalents" in relation to the compounds of the invention indicates compounds which on administration are converted in vivo into the antibiotic compound. Such equivalent compounds include biologicaily acceptable, metabolically labile ester derivatives, for example, acyloxymethyl esters, e.g. lower alkanoyloxymethyl esters such as acetoxymethyl, acetoxyethyl or pivaloyloxymethyl esters.

Particularly preferred compounds according to the present invention by virtue of their particularly high levels of activity against Escherichia colt and Proteus organisms include the following compounds and their non-toxic salts and physiologically acceptable equivalents: (6 R,7 R)-3-acetoxymethyl-7-[Z- 2-(fur-2-yl)-2- (tetrazol-5-ylmethoxyimino)acetamido] ceph-3em-4-carboxylic acid and (6R,7R)-3 carbamoyloxymethyl-7-[Z-2-(fur-2-yl)-2- (tetrazol-5-ylmethoxyi mino)aceta mido]ceph-3em-4-carboxylic acid. These compounds may be used, inter alia, as their sodium salts.

The compounds of formula (I) may be used for treating a variety of diseases caused by pathogenic bacteria in human beings and animals, such as respiratory tract and urinary tract infections.

The compounds according to the invention may be prepared by any convenient method, for example by techniques analogous to those described in British Patent Specification No.

1,399,086.

Thus, according to a further feature of the present invention we provide a process for the preparation of a compound of formula (I) above or a non-toxic salt or physiologically acceptable equivalent thereof which comprises either (A) condensing a compound formula

[wherein R is as defined above;B is > S or > SoO (a- or P-); R2 represents hydrogen or a carboxyl blocking group, e.g. the residue of an esterforming aliphatic or araliphatic alcohol or an ester-forming phenol, silanol or stannanol (the said alcohol, phenol, silanol or stannanol preferably containing 1-20 carbon atoms) or a symmetricai or mixed anhydride group derives from an appropriate acid; and the dotted line bridging the 2-, 3- and 4- positions indicates that the compound is a ceph-2-em or ceph-3-3em compound] our a salt, e.g. an acid addition salt such as a hydrochloride, hydrobromide, sulphate, nitrate, phosphate, methane sulphonate or tosylate, or an N- silylated derivative thereof, with an acid of formula

[wherein R1 is as defined above and Z' represents a group of formula

(wherein R3 is an N-protecting group)] or with an acylating agent corresponding to the said acid; or (B) reacting a compound of the formula

(wherein R', R2, B and the dotted line are as defined above and Z" is a group selected from the groups Z and Z' as defined above) with an acylating agent serving to form an acetoxymethyl, carba moyloxymethyl, N-methyl carbamoyloxymethyl or N-(2chloroethyl)carbamoyloxymethyl group at the 3position; whereafter, if necessary and/or desired, in each instance, any of the following reactions (C), in any appropriate sequence are carried out: i) removal of any N-protecting and/or carboxyl blocking groups; ii) conversion of a 2 isomer into the desired A3 isomer; iii) reduction of a compound wherein B is > SoO to form a compound wherein B is > S; and iv) conversion of a carboxyl group into a physiologically acceptable ester function; and finally (D) recovering the desired compound of formula (I) or a non-toxic salt or physiologically acceptable equivalent thereof, if necessary after separation of isomers.

In processes (A) and (B) above the subsequent removal of the N-protecting group R3 may result in a tautomeric mixture of the deprotected tetrazol-5-yl group.

Base salts may te formed by reaction of the cephalosporin acid with for example sodium 2ethylhexanoate or potassium 2-ethylhexanoate.

Biologically acceptable ester derivatives may be formed using conventional esterifying agents.

Acylating agents which may be employed in the preparation of compounds of formula (I) include acid halides, particularly acid chlorides or bromides. Such acylating agents may be prepared by reacting an acid (III) or a salt thereof with a halogenating agent e.g. phosphorus pentachloride, thionyl chloride or oxalyl chloride.

Treatment of the sodium, potassium or triethylammonium salt of the compound of formula (III) with oxalyl chloride is advantageous in that under these conditions isomerisation is minimal.

Acylations employing acid halides may be effected in aqueous and non-aqueous reaction media, conveniently at temperatures of from -50 to +500C, preferably -20 to +300C, if desired in the presence of an acid binding agent. Suitable reaction media include agueous ketones such as aqueous acetone, esters, such as ethyl acetate halogenated hydrocarbons such as methylene chloride, amides such as dimethylacetamide, nitriles such as acetonitrile, or mixtures to two or more such solvents. Suitable acid binding agents include tertiary amines (e.g. triethylamine or dimethylaniline), inorganic bases (e.g. calcium carbonate or sodium bicarbonate), and oxiranes such as lower 1,2-alkylene oxides (e.g. ethylene oxide or propylene oxide) which bind hydrogen halide liberated in the acylation reaction.

Acids of formula (III) may themselves be used as acylating agents in the preparation of compounds of formula (I). Acylations employing acids (III) are desirably conducted in the presence of a condensing agent, for example a carbodiimide such as N,N'dicyclohexylcarbodiimide.

Acylation may also be effected with other amide-forming derivatives of acids of formula (III) such as, for example, an acitivated ester, a symmetrical anhydride or a mixed anhydride (e.g.

with pivalic acid or formed with a haloformate such as a lower alkylhaloformate). An activated ester may conveniently be formed in situ using for example 1 -hydroxybenzotriazole in the presence of a condensing agent as set out above.

Acylation reactions involving the free acids or their above-mentioned amide-forming derivatives are desirably effected in an anhydrous reaction medium, e.g. methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran.

Acylation of 3-hydroxymethyl compounds of formula (IV) may be effected by conventional methods. Thus, for example a 3-hydroxymethyl cephalosporin may be reacted with an isocyanate of formula Ra. NCO (wherein R8 represents a labile substituent group or a methyl or 2-chioroethyl group) to give a compound containing a 3-position substituent having the formula -CH2O . CONTRA (wherein RB has the above defined meaning). Where Ra is a labile substituent this substituent may if desired subsequently be cleaved, e.g. by hydrolysis, to form a 3-carbamoyloxymethyl group.Labile groups Ra which are readily cleavable upon subsequent treatment include chlorosulphonyl and bromo-sulphonyl; halogenated lower alkanoyl groups such as dichloroacetyl and trichloroacetyl; and halogenated lower alkoxycarbonyl groups such as 2,2,2trichloroethoxy-carbonyl. These labile Ra groups may generally be cleaved by acid or base catalysed hydrolysis (e.g. by base catalysed hydrolysis using sodium bicarbonate).

Acetylation of 3-hydroxymethyl compounds of formula (IV) may be effected by conventional methods, for example in an analogous manner to that described in British Patent Specification No.

1,141,293, i.e. by aralkylating the 4-carboxy group, acetylating the 3-hydroxymethyl group of the protected compound and subsequently removing the aralkyl group.

3-Hydroxymethyl starting materials of formula (IV) for use in process (B) above may be prepared for example by the method described in British Patent No. 1,474,519, and U.S. Patent No.

3,976,546.

A2-Cephalosporin ester derivatives obtained in accordance with the process of the invention may be converted into the corresponding t3 derivative by, for example, treatment of the A2 ester with a base.

A ceph-2-em reaction product may be oxidised to yield the corresponding ceph-3-em 1-oxide, for example by reaction with a peracid; the resulting sulphoxide may, if desired, subsequently be reduced as described hereafter to yield the corresponding ceph-3-em-sulphide.

Where a compound is obtained in which B is > S ,0 this may be converted to the corresponding sulphide by, for example, reduction of the corresponding acyloxysulphonium or alkyloxysulphonium salt prepared in situ by reaction with e.g. acetyl chloride in the case of an acetoxysulphonium salt, reduction being effected by, for example, sodium dithionite or by iodide ion as in a solution of potassium iodide in a water miscible solvent e.g. acetic acid, tetrahydrofuran, dioxan, dimethylformamide, dimethylacetamide or acetone. The reaction may be effected at a temperature of --200 to +500C.

It should be appreciated that in some of the above transformations it may be necessary to protect any sensitive groups in the molecule of the compound in question to avoid undesirable side-reactions.

Where a compound of formula (I) is obtained as a mixture of isomers, the syn isomer may be obtained by, for example, conventional methods such as crystallisation or chromatography.

The acids of formula (III) may be prepared, for example, by etherification of a compound of formula

(wherein R' is as defined above and R4 represents hydrogen or a carboxyl blocking group) with a compound of formula Hal . CH2Z' (Ví) (wherein Z' is as defined above and Hal represents a halogen atom such as chlorine, bromine or iodine), followed by removal of any carboxyl blocking group R4. The etherification is desirably carried out in the presence of a base, e.g. potassium t-butoxide or sodium hydride, and is preferably conducted in an organic solvent, for example dimethylsuphoxide, a cyclic ether such as tetrahydrofuran or dioxan, or an N,Ndisubstituted amide such as dimethylformamide.

Under these conditions the configuration of the oximino group is substantially unchanged by the etherification reaction.

The compound of formula (Vl) employed as starting material in the above etherification may, for example, be prepared by reacting a 5halomethyltetrazole with an N-protecting agent to introduce an N-protecting group at the 1- and 2positions of the tetrazole ring whereby a mixture of compounds of formulae

is produced. This mixture may be used as such in the above etherification reaction or the mixture may be separated and one or other of the separated isomers employed in the etherification reaction.

The above N-protection reaction may be carried out in conventional manner.

Advantageously, 5-chloromethyltetrazole is reacted with diphenyldiazomethane to introduce diphenylmethyl as the protecting group R3.

Suitable carboxyl blocking groups are well known in the art, a list of representative blocked carboxyl groups being included in British Patent No. 1399086. Preferred blocked carboxyl groups include aryl lower alkoxycarbonyl groups such as p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl and diphenyl methoxycarbonyl; lower alkoxycarbonyl groups such as t-butoxycarbonyl; and lower haloalkoxycarbonyl groups such as 2,2,2trichloroethyoxycarbonyl. The carboxyl blocking group may subsequently be removed by any of the appropriate methods disclosed in the literature. For example, acid-, base- or enzymically-catalysed hydrolysis and reductive methods are applicable in many cases.

The N-protecting group R3 may also be selected from such groups which are well known in the art, aryl lower alkyl groups such as those specifically mentioned above as carboxyl blocking groups being especially preferred. These groups may be removed in conventional manner.

The antibiotic compounds of the invention may be formulated for administration in any convenient way, by analogy with other antibiotics and the invention therefore includes within its scope pharmaceutical compositions comprising an antibiotic compound in accordance with the invention adapted for use in human or veterinary medicine. Such compositions may be presented for use in conventional manner with the aid of any necessary pharmaceutical carriers or excipients.

The antibiotic compounds according to the invention may be formulated for injection and may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for reconstitutibn with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

The antibiotic compounds may also be presented in a form suitable for absorption by the gastro-intestinal tract, e.g. as tablets or capsules.

The antibiotic compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glyceride.

Compositions for veterinary medicine may, for example, be formulated as intramammary preparations in either long acting or quick-release bases.

The compositions may contain from 0.1% upwards, e.g. 0.1-99%, preferably from 1060% of the active material, depending on the method of administration. When the compositions comprise dosage units, each unit will preferably contain 50-1 500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 500 to 5000 mg per day, depending on the route and frequency of administration, although in treating some infections higher daily doses may be required.

The antibiotic compounds according to the invention may be administered in combination with other therapeutic agents such as antibiotics, for example penicillins or other cephalosporins.

The following examples illustrate the invention.

All temperatures are in OC.

Preparation 1 1 -Diphenylmethyl-5-chloromethyltetrazole 5-Chioromethyltetrazole (6 g) was added to a stirred solution of diphenyldiazomethane (50 mmoles) in 40-60 petrol (190 mls) and the solution was warmed to 2530 for 3 hours.

The solid was filtered off, washed with petrol and dried giving 1-diphenylmethyl-5- chloromethyltetrazole (6.5 g). m.pt. 90--920, AmaX(EtOH) 252.5 ( 4301, 2W(E 540)262.5 nm ( 480), vm"t(Nujol) 1598, 598,1518,1491 cam~' (aromatic --C=C-), z (DMSOd6) 4.61 (CICH2).

2.54 (Ph2CH), 2.6 (Ph).

Evaporation of the filtrate gave 2diphenylmethyl-5-ch loromethyltstrazole as a yellow oil; z(DMSOd6) 2.21 (Ph2CH), 2.59 (Ph), 4.93 (CICH2-).

Preparation 2 Z-2-( Fur-2-yl)-2-[(1 -diphenyl methyltetrazol-5yl)-methoxyimino] acetic acid A solution of potassium tert-butoxide (5.6 g) in dimethylsulphoxide (20 mls) were added to a stirred solution of Z-2-(fur-2-yl)-2-hydroxyimino acetic acid (3.5 g) in dimethylsulphoxide (20 mis)i and the mixture was stirred for 20 minutes. A solution of 1-diphenyl-methyl-5chloromethyltetrazole (6.4 g) in dimethylsulphoxide (25 mls) was added and the mixture was stirred for a further 4 hours. The resulting solution was poured into 2M hydrochloric acid and extracted with ethyl acetate (4x30 mix). The organic solution was extracted with saturated sodium bicarbonate solution (3x50 mis) and the extracts were washed with ethyl acetate (20 mix). The aqueous layer was acidified with 2M hydrochloric acid, extracted into dichloromethane (3x50 mls) and the extracts were dried over sodium sulphate and evaporated to give the title compound as a yellow foam (5.8 g); (EtOH) 270 nm (E 14100); vmax(CHBr3) 1248 (CO2H), 1 596, 1499, 1483 (C=C aromatic), 1 745 cm-1 (C=O), acid);T (DMSOd6) values include 2.03, 3.1-3.35 (furyl), 4.3 (OCK2), 2.52 (Ph2CH), 2.6 (Ph).

Example 1 (a) tert-Butyl (6R,7R)-3-acetoxymethyl-7-(Z-2- (fur-2-yl)-2-[(1 -diphenyl methyltetrazol-5-yl ) methoxyimino]aceta mido ]-ceph3-em-4- carboxylate A solution of Z-2-(fur-2-yl)-2[(1 diphenylmethyltetrazol-5-yl)-methoxyimino] acetic acid (0.8 g) in dichloromethane (20 mls) was added slowly to a stirred solution of tert-butyl (6R,7R)-7-amino-3-acetoxymethylceph-3-em-4- carboxylate (0.7 g) and dicyclohexylcarbodiimide (0.5 g) in dichloromethane (20 mls) and the mixture was stirred for 3 hours. The mixture was filtered, the filtrate was evaporated and the residue was dissolved in ethyl acetate (70 mls).

The solution was filtered and washed with 2M hydrochloric acid (2x30 mls) and with sodium bicarbonate solution (50 mls), dried over sodium sulphate and evaporated. The residue was purified on a column of silica gel (120 g), eluding with a mixture of toluene and ether (2:1) to give the title compound (0.35 g); vmax(CHBr3) 3350 (NH), 1784 ss(lactam), 1720, 1228 (ester), 1690, 1520 cm-1 (amide), T (DMSO-d,) values include 2.1,3.36 (furyl), 4.64 (-OCH2-), 2.71 (Ph), 4.24, 4.86 (7H,6H), 8.0 (-OAc), 8.54 (tBu), 5.1, 5.45 (3-CH2-).

(b) (6R,7R)-3-Acetoxymethyl-7-[Z-2-(fur-2-yl) 2-(tetrazol-5-ylmethoxyi mino) acetamido] ceph-3-em-4-carboxylic acid tert-Butyl (6 R,7 R)-3-acetoxymethyl-7-[Z-2- (fur-2-yl)-2-[( 1 -diphenylmethyltetrazol-5-yl) methoxyimino] acetamido} ceph-3-em-4 carboxylate (2.9 g) was stirred for 35 minutes with trifluoroacetic acid (60 mls) and anisole (30 mis) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mls) and the solution was extracted with saturated sodium bicarbonate solution (3x50 mls).The extracts were acidified with 2M hydrochloric acid, extracted with ethyl acetate (4x40 mls) and the extracts were dried over sodium sulphate and evaporated to a volume of 10 mls. The solution was added dropwise to stirred petroleum ether (150 mls,b.p. 40-60), the precipitated solid was filtered off and dried to give the title compound(1.6 g); [a]o19=+37.3o (c 0.73 DMSO); AmaX(EtOH) 274 nm (E 17800);; vmax(Nujol) 3700-2300 (NH, OH),1784 (p- lactam), 1729 (ester) 1 685, 1 540 cm

T (DMSO-d6) 2.16,3.21, 3.36 (furyl), 4.5 (OCH2C-), 4.16,4.82 (7H,6H), 0.25 (QNK-), 6.4 (2-CH2-), 4.97, 5.3 (,3-CH2-) 7.96 (OAc).

Example 2 (a) Diphenylmethyl (6R,7R)-3carba moyloxymethyl-7-[Z-2-fur-2-yl)-2-[(1 diphenylmethyltetrazol-5-yl) methoxy imino]acetamido)ceph-3-em-4-carboxylate This compound was prepared in a similar manner to Example 1 (a) from diphenylmethyl (6R,7R)-7-amino-3-carbamoylmethylceph-3-em- 4-carboxylate. AmaX(EtOH) 278 nm (E 18000), vmax(Nujol) 1780(-Iactam), 1720, 1718 (-CO2R, OCONH2), 3470,3350 (NH, NH2), 1680, 1530 cm-' (-CONH-);; T (DMSO-d8) 2.3-3.0 (Ph2CH), 4.47 (-OCH2-), 2.1, 3.28, 3.35 (furyl), 4.1,4.7 (7H, 6H), 0.03 (CONH), 6.3, 6.59 (2-CH2-), 5.16, 5.4 (3-CH2), 3.3 (NH2).

(b) Sodium (6R,7R)-3-Carbamoyloxymethyl-7- [Z-2-(fur-2-yl)-2-(tetrazol-5-ylmethoxyimino) aceta mido]ceph-3-em-4-carboxylate Diphenylmethyl (6R,7R)-3 ca rbamoyloxymethyl-7 {Z-2-(fu r-2-yl)-2-[( 1 - diphenylmethyltetrazol-5-yl) methoxyimino] acetamidolceph-3-em-4-carboxylate (1 g) was stirred at 0 with trifluoroacetic acid (6 mls), and anisole (3 mls) for 15 minutes. The solution was poured into sodium bicarbonate solution (100 mls), washed with ethyl acetate (2x25 mls), acidified with 2M hydrochloric acid and extracted with ethyl acetate (3x20 mls).The organic solution was dried over sodium sulphate and evaporated to give (6R,7R)-3-carbamoyloxymethyl-7-[Z-2- (fur-2 -yl)-2-[( 1 -diphenylmethyltetrazol-5yl)methoxyimino]acetamido)ceph-3-em-4- carboxylic acid. This was stirred with trifluoro acetic acid (6 mls) and anisole (3 mls) for 35 minutes and the resulting solution was worked up as described above. The residue was dissolved in a little acetone and the solution was added dropwise to petroleum ether (100 mis, b.p. 40- 60) with stirring. The precipitate was filtered off and dried. A solution of the solid in acetone (20 mis) was treated with a solution of sodium ethylhexanoate (equivalent) in acetone (3 mls) and the precipitate was filtered off. The solid was dissolved in water (50 mls) and the solution was filtered and freeze-dried to give the title compound (0.12 g);#max(H2O) 277.5 nm (E 13600); Pmt,x(Nujol) 3460-3240 (NH, NH2), 1767 (#-lactam),1710 (-OCONH2),1610 (-CO2-), 1680 cm-1 (-CONH-); T(D20) 4.43 (-OCH2-), 2.27, 3.3, 3.02 (furyl), 4.19,4.81 (7H, 6H), 6.39, 6.7 (2-CH2-), 5.06, 5.3 (3-CH2-).

Claims (14)

Claims

1. Antibiotic compounds of the general formula

twherein R1 is a furyl or thienyl group; R is a methyl amino, methylamino or 2-chloroethylamino group; and Z is a tetrazol-5-yl group] and nontoxic salts and physiologically acceptable equivalents thereof, the compounds being syn isomers or existing as mixtures of syn and anti isomers containing at least 75% of the syn isomers.

2. A compound as claimed in claim 1 existing as a mixture of syn and anti isomers containing at least 90% of the syn isomer.

3. A compound as claimed in claim 2 which is a syn isomer essentially free from the corresponding anti isomer.

4. (6R,7 R)-3-Acetoxymethyl-7-[Z-2-(fur-2-yl)2-(tetrazoi-5-yl methoxyi mino)acetamido] ceph-3em-4-carboxylic acid and non-toxic salts and physiologically acceptable equivalents thereof.

5. (6R,7 R)-3-Carba moyloxymethyl-7-[Z-2-(fur2-yl)-2-(tetrazol-5ylmethoxyimino)acetamido]ceph-3-em-4carboxylic acid and non-toxic salts and physiologically acceptable equivalents thereof.

6. A process for the preparation of a compound of formula (I) (as defined in claim 1) or a non-toxic salt or physiologically acceptable equivalent thereof which comprises either (A) condensing a compound of formula

[wherein R is as defined above; B is > S or > SoO (a- or p-); R2 represents hydrogen or a carboxyl blocking group; and the dotted line bridging the 2-, 3- and 4- positions indicated that the compound is a ceph-2-em or ceph-3-em compound] or a salt or an N-silylated derivative thereof, with an acid of formula

[wherein R' is as defined above and Z' represents a group of formula

(wherein R3 is an N-protecting group or with an acylating agent corresponding to the said acid; or (B) reacting a compound of the formula

(wherein R1, R2, B and the dotted line are as defined above and Z" is a group selected from the groups Z and Z' as defined above) with an acylating agent serving to form an acetoxymethyl, carbamoyloxymethyl, N methyl carba moyl oxymethyl or chloroethyl)carbamoyloxymethyl group at the 3position, whereafter, if necessary and/or desired, in each instance, any of the following reactions (C), in any appropriate sequence are carried out: i) removal of any N-protecting and/or carboxyl blocking groups; ii) conversion of a 2 isomer into the desired A3 isomer; iii) reduction of a compound wherein B is > SoO to form a compound wherein B is > S; and iv) conversion of a carboxyl group into a physiologically acceptable ester function; and finally (D) recovering the desired compound of formula (I) or a non-toxic salt or physiologically acceptable equivalent thereof, if necessary after separation of isomers.

7. A process as claimed in claim 6 wherein a compound of formula (II) is condensed with an acid halide corresponding to the acid of formula (III)

8. A process as claimed in claim 7 wherein the condensation is effected in the presence of an acid binding agent comprising a tertiary amine, an inorganic base or an oxirane.

9. A process as claimed in claim 6 wherein a compound of formula (II) is condensed with a free acid of formula (III) in the presence of a condensing agent comprising a carbodiimide.

10. A process as claimed in claim 6 wherein a compound of formula (IV) is reacted with a carbamoylating agent comprising an isocyanate of formula Ra. . NCO (wherein Ra represents a labile substituent group or a methyl or 2-chloroethyl group).

11. A process as claimed in claim 6 substantially as herein described.

1 2.'A process for the preparation of compounds of formula (I) (as defined in claim 1) substantially as herein described in either of the Examples.

13. Compounds of formula (I) (as defined in claim 1) whenever prepared by a process as claimed in any of claims 6 to 12.

14. A pharmaceutical composition comprising, as active ingredient, at least one compound as claimed in any of claims 1--5 and 13 in association with at least one pharmaceutical carrier or excipient.