GB2094304A - beta -Lactam antibiotics - Google Patents

Abstract

beta -Lactam antibiotics of the formula: <IMAGE> wherein R is fluoro, chloro, bromo or iodo; R<3> is a hydrogen atom or a C1-6 alkyl, aryl or aralkyl group; and R<5> and R<6> are the 7-and 3- side chains respectively of a beta -lactamase sensitive cephalosporin antibiotic.

Description

SPECIFICATION ss-Lactam antibiotics This invention relates to ss-lactam antibiotics and in particular to methylene bis-esters of certain cephalosporins with a 6-ss-halopenicillanic acid fi-lactamase inhibitor, to methods for the preparation of such. compounds and to pharmacetical compositions containing such compounds for treating patients suffering from infectious diseases.

According to the specification of British patent application no. 2047684A there are disclosed 6-ss-halopenicillanic acids of the formula:

wherein R is fluoro, chloro, bromo or iodo, and R1 is hydrogen or an ester-forming residue readily hydrolysable in vivo. Such compounds are able to inhibit the action of fi-lactamase enzymes and are thus useful to enhance the effectiveness of penicillin and cephalosporin antibiotics against strains of bacteria which produce fi-lactamase enzymes and which would otherwise be capable of inactivating the antibiotics. Particularly useful in this respect is 6-ss- iodopenicillanic acid and salts thereof.

We have now discovered that compounds in which the ester-forming residue R1 is a cephalosporin antibiotic linked to the 6-P-halopenicillanic acid as a methylene bis-ester are useful broad-spectrum antibiotics combining in one molecule the properties of a potent ss- lactamase inhibitor and a cephalosporin antibiotic.Although fi-lactamase inhibitors can generally be co-administered with the antibiotic we have discovered that it is advantageous to link these molecules chemically in this way because the resulting compounds are hydrolysed during or after administraton of the drug by enzymes which are present in the gut wall, the blood stream, plasma or liver of the patient and the sslactam antibiotic and the fi-lactamase inhibitor are thus released into circulation at the same time, and the advantageous synergistic effect of the ss- lactamase inhibitor is obtained.

Thus according to the present invention there are provided compounds of the formula:

wherein R is fluoro, chloro, bromo or iodo; R3 is a hydroen atom or a lower alkyl, aryl or aralkyl group; and R5 and R6 are the 7- and 3- side chains respectively of a fi-lactamase sensitive cephalosporin antibiotic.

Especially useful compounds are those wherein R is iodo. R5 and R6 are the side chains of cephalosporin antibiotics which are known to be of value in the treatment of bacterial infections and which are known to be inactivated by fi-lactamase containing microorganisms and which are, therefore, advantageously used in conjuction with a fi-lactamase inhibitor.

Whether any particular cephalosporin antibiotic is susceptible to fi-lactamase enzymes will be well known to those skilled in the art and is readily determined by measuring the in vitro activity of the cephalosporin against strains of bacteria known to produce fi-lactamase enzymes. Where the cephalosporin is inactivated, the concentration of the cephalosporin required to inhibit growth of the particular bacteria in standard tests will be significantly higher than that required to inhibit strains of the bacteria which do not produce fi-lactasmase enzymes.

Examples of R5 groups which may be present in the compounds of formula II include the following:

N # C-CH, CONH

Examples of R6 group which may be present in the compounds of formula II include the following: -CH3 -H -C1 -CH2OCOCH3 -OCH3

-CH20CONH2

Particularly useful compounds of formula II are those in which the group R5 and R6 are those present as the 7- and 3-side chains respectively of cefamandole, cefazolin, cephalothin, cefaperazone or cephaloglycin.

The term lower alkyl as used herein means a C-I to C-6 straight or branched chain alkyl radical, and aryl stands for an aromatic monocyclic or bicyclic carbocyclic radical. Compounds in which R3 is other than hydrogen, give rise to diastereomeric forms and the invention includes all such diastereomers as well as mixtures thereof.

In the formulae a broken line indicates that the substituent is below the plane of the bicyclic nucleus. Such a substituent is said to be in the ou-configuration. Conversely wedge attachment of a substituent indicates that it is above the plane of the nucleus and is in the fl-configuration.

The compounds of the formula II may be prepared by a number of different processes according to the invention. In one process they are prepared from a compound of the formula:

wherein R and R3 are as previously defined and X is a leaving group, particularly a halogen atom, by reacting with a salt of the cephalosporin of formula:

wherein R5-and R6 are as previously defined and Ms is a cation and wherein any reactive group in R5 or R6 may optionally be protected. Suitable salts are the sodium, potassium or tetrabutylammonium salts.

The reaction is performed with the reactants, generally in equimolar proportions, dissolved in an inert organic solvent, for example N,N-dimethylformamide or ethyl acetate. The reaction is conveniently stirred at a temperature of from 0 C to room temperature and is generally complete within a period of 1 5 minutes to 2 hours under these conditions. The product is isolated in a conventional manner, for example by solvent extraction, washing to remove water-soluble impurities, drying and evaporation of the solvent. Further purification of the product may be achieved, if desired, by recrystallization or by chromatography.

In an alternative process, a derivative of the cephalosporin of the formula:

wherein R3, R5, R6 and X are as previously defined, is reacted with a salt of 6-ss-halopenicillanic acid in an identical manner to that described above for the compound of formula (III).

In another process according to a further aspect of the invention, the salt of the cephalosporin of formula (IV) is reacted with a compound of the formula:

wherein R3 and X are as previously defined and R4 is perchloro or perfluoroalkyl group of from 1 to 4 carbon atoms; and the resulting product is reacted with halide ion (generally as the alkali metal halide) to give the compound of formula (II). Particularly useful in this respect are the compounds of formula (VI) wherein R4 is fluoro or a trifluoromethyl group.

The compounds of formula (Vl) and methods and conditions for performing the displacement reaction with halide ion are described in our co-pending U.K. patent application no. 8036325 (Serial No. 2086880).

The starting materials of formulae (III), (V) and (VI) may be prepared from the corresponding salt of the 6-ss-halopenicillanic acid, cephalosporin or 6-ss-substituted-penicillanic acid respectively by reacting with a compound of the formula:

wherein R3 and X are as previously defined and Q is a bromine or iodine atom, or an alkylsulphonyloxy, arylsulphonyloxy or chlorosulphonyloxy group, Q being a better leaving group than X.

Thus the compound of formula (VII) may be for example a chloroiodoalkane and reaction with the appropriate salt gives the compound of formula (III), (V) or (VI) wherein X is chloro. In the case of the compound of formula (VI) this may be further reacted as described in our co-pending application no. 8036325 (Serial No. 2086880); thus, for example, reaction with sodium iodide yields the compound of formula (III), wherein R and X are both iodo.

The cephalosporins of formula (IV) are all known compounds, their salts may be prepared from the free acid by neutralization with one equivalent of the appropriate base.

The compounds of the invention are valuable antibiotic agents combining in the same molecule a potent fi-lactamase inhibitor and a cephalosporin antibiotic of value for the treatment of a variety of infectious diseases. The compounds may be administered alone but are preferably given as a pharmaceutical formulation. Thus the invention also provides a pharmaceutical composition comprising a compound of the formula (II) together with a pharmaceutically acceptable diluent or carrier.

The carrier or diluent is chosen on the basis of the intended mode of administration. For example, for oral administration, the antibacterial compounds of this invention can be used in the form of tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions or suspensions, in accordance with standard pharmaceutical practice. The proportion of active ingredient to carrier will naturally depend on the chemical nature, solubility and stability of the active ingredient, as well as the dosage contemplated. In the case of tablets for oral use, carriers which are commonly used include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, and lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are also commonly used in tablets.For oral administration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring agents can be added. For parenteral administration, which includes intramuscular, intraperitoneal, subcutaneous, and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic with blood.

As indicated earlier, the antibacterial compounds of this invention are of use in human subjects and the daily dosages to be used will be comparable with other, clinically-used, cephalosporin antibiotics. The prescribing physician will ultimately determine the appropriate dose for a given human subject, and this can be expected to vary according to the age, weight and response of the individual patient as well as the nature and the severity of the patient's symptoms. The compounds of this invention will normally be used orally at dosages in the range from about 20 to about 200 mg. per kilogram of body weight per day, and parenterally at dosages from about 10 to about 200 mg. per kilogram of body weight per day, usually in divided doses. There may of course be individual cases where it may be necessary to use doses outside these ranges.

The following examples and preparations are provided solely for further illustration. Infrared (IR) spectra were measured as potassium bromide discs (KBr discs) and diagnostic absorption bands are reported in wave numbers (cm-1). Nuclear magnetic resonance spectra (NMR) were measured at 60 MHz for solutions in deuterated solvents and peak positions are reported in parts per million downfield from tetramethylsilane. The following abbreviations for peak shapes are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.

EXAMPLE I 6fi-Iodopeniclllanoyloxymethyl 7ss-(2-formyloxy-2-phenylacetamido)-3- {( 1 -methyl- 1 H -tetrazol 5yl)thiomethyl} -ceph-3-em-4-carboxylate lodomethyl 6ss-iodopenicillanate (230 mg) in dimethylformamide (DMF) (5 ml) was treated with a solution of cefamandole sodium salt (300 mg) in DMF (5 ml) at 0 C for 30 minutes. The solution was added to a mixture of ethyl acetate (40 ml) and water (40 ml) and the ethyl acetate extract washed with water (2 x 20 ml). The solution was dried (MgSO4) and the solvent evaporated in vacuo to give a residue which was triturated with ether-petroleum ether (BP 40-60"C) to give the product (230 mg) as a white solid.

M.P. 105"C (dec) I.R. 1780 cm-1 N.M.R. (CD3COCD3) 8:1.52 (3H, s), 1.69 (3H, s), 3.74 (2H, s), 3.98 (3H, s), 4.40 (2H, d, J = 7), 4.61 (H, s), 5.07 (H, d, J = 5), 5.49 (H, d, J =4), 5.70-6.13 (4H, m), 6.22 (H, s), 7.3-7.75 (5H, m), 8.3 (H, s), 8.36 (H, d, J = 8).

EXAMPLE 2 6fi-lodopenicillanoyloxymeth VI 7fi-(1 H )4etrazol- I -ylacetamido-3-[(5-methyl- 3, 44h iadiazol-2-yl)- thiomethyl]-ceph-3-em-4-carboxylate The procedure of Example 1 was followed but using cefazolin (sodium salt) and 6ss- iodopenicillante to give the title compound.

M.P. 124-126"C /. 1780 cm-' N. M. R. CD3COCD3. S:1 .51 (3H, s), 1.69 (3H, s), 2.71 (3H, s), 3.82 (centre of ABq, J = 18), 4.18 and 4.78 (H and H, centres of AB doublets J = 15), 4.64 (H, s), 5.17 (d, J = 5), 5.50 (3H, m CH2CONH and pen C(5)-H), 5.70-6.15 (4H, m), 8.54 (H, d, J =8), 9.16 (H, s).

EXAMPLE 3 6ss-lodopenicillanoyloxymethyl 7ss-thien-2-ylacetamido-3-acetoxy methyl-ceph-3-em-4 carboxylate The procedure of Example 1 was followed but using cephalothin (sodium salt) and 6ss- iodopenicillanate to give the title compound as a gum.

/. 1790 cm-' N.M.R. (CDCI3).8:1.46 (3H, s), 1.66 (3H, s), 2.05 (3H, s), 3.46 (2H, broad s), 3.81 (2H, s), 4.56 (H, s), 4.90 (H, d, J = 4), 5.01 (2H, br. s), 5.40 (H, d, J = 5), 5.65 (H, d, J = 5) 5.80-5.99 (3H, m), 6.9-7.3 (3H, m).

EXAMPLE 4 6sslodopenicillanoyloxymethyl 7ss-[D-2-(4-ethy-2,3-dioxo-1-piperazinecarboxamido)-2-(4-hydrox- y)phenylacetamidoj-3-f( 1 -methyl- 1 H tetrazol-5-yl)thiomethyl]-ceph-3-em-4-carboxylate A suspension of cefaperazone sodium salt (404 mg) in a solution of iodomethyl 6ss- odopenicillanate (520 mg) in acetone (4 ml) was stirred for 24 hours. The solvent was diluted with ethyl acetate (30 ml) and washed with water (2 X 10 ml). The solvent was dried (MgSO4) and removed in vacuo. The product was purified by chromatography over silica gel and obtained as a gum.

I. R. 1780 cm - 1 N.M.R. CD3COCD3 #:1.16 (3H, t, J = 7), 1.51 (3H, s), 1.7 (3H, s), 3.49 (2H, q, J = 7), 3.7 (2H, br.s), 3.67 and 3.8 (H and H, centres of AB doublets J = 20), 3.98 (3H, s), 4.04 (2H, m), 4.26 and 4.51 (H and H, ABq J = 15), 4.62 (H, s), 5.05 (H, d, J = 4.8), 5.49 (H, d, J = 3.9), 5.57 (H, d, J = 6.7), 5.86 (H, dd, J = 4.8, 8.6), 5.93 (H, d, J = 3.9), 5.98 and 6.02 (H and H, ABq, J = 5.8), 6.82 (2H, d, J = 10), 7.33 (2H, d, J = 10), 8.32 (H, d, J = 8.6), 9.87 (H, d, J = 6.7).

Claims (3)

1. Compounds of the formula (II) as hereinbefore defined.

2. Pharaceutical compositions comprising a compound of the formula (II) together with a pharmaceutically acceptable diluent or carrier.

3. Processes for preparing the compounds of the formula (II) as hereinbefore described.