GB2089798A - B-Lactam antibiotics - Google Patents

Abstract

B-Lactam antibiotics of the formula: <IMAGE> wherein R is fluoro, chloro, bromo or iodo; R<2> is a phenyl or phenoxy group; and R<3> is a hydrogen atom or a lower alkyl, aryl or aralkyl group; pharmaceutical compositions thereof and processes for their preparation are described.

Description

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

According to the specification of British patent application GB 2047684A there are disclosed 6-ss-halopenicillanic acids of the formula:

wherein R is fluoro, chloro, bromo or iodo, and R' 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 particularly useful compounds are those in which the esterforming residue R1 may be penicillin V or penicillin G linked to the 6-fi-halo-penicillanic acid as a methylene bis ester. Although plactamase 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 this enables the resulting compounds to be hydrolysed during or after administration of the drug by enzymes which are present in the gut wall, the blood stream, plasma or liver of the patient.The Blactam antibiotic and the sslactamase inhibitor are thus released into circulation at the same time, and the advantageous synergystic effect of the fi-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; R2 is a phenyl or phenoxy group; and R3 is a hydrogen atom or a lower alkyl, aryl or aralkyl group.

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 a!l 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 a-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 penicillin G or penicillin V. 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 re-crystatlization or by chromatography.

In an alternative process, a derivative of penicillin V or pencillin G of the formula:

wherein R2, R3 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 (Ill).

In another process according to a further aspect of the invention, the salt of penicillin V or penicillin G is reacted wiTh a compound of the formula:

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

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

The starting materials of formula (III), (IV) and (V) may be prepared frrom the corresponding salt of the 6-phalopenicillanic acid, penicillin or 6-a-perhalosulphonyloxy penicillanic acid respectively by reacting with a compound of the formula:

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

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

The compounds of the invention are valuable antibiotic agents combining in the same molecule a potent ss-lactamase inhibitor and a widely used penicillin 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, penicillin 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 chloroform (CDCl3) 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 1 613-lodopenicillanoyloxymethyl 6ss-phenylacetamidopenicillanate A solution of 6ss-phenylacetamidopenicillanate sodium salt (0.5 g) and (0.41 g) in N,Ndimethylformamide (2 ml) was stirred at 0-5"C for 1 5 minutes. The solution was diluted with ethyl acetate (50 ml), washed with water (3 X 50 ml), and dried over Na2SO4. The solvent was evaporated under vacuum to afford the title compound as a gum (510 mg).

IR 1780 cm-1.

NMR (CDCl3), 1.45 (9H,s), 1.66(3H,s), 3.59 (2H,s), 4.36 (H,sl 4.5 (H,s), 5.25-5.73(4H,m), 5.81 (2H,s), 6.4 (H,d,J = 8), 7.28 (5H,s).

Example 2 6sslodopenicillanoyloxymethyl 6ss-phenoxyacetamidopenicillanate The procedure of Example I was followed but using the sodium salt of 6ss-phenoxyacetamido- penicillanic acid (0.4 g) and iodomethyl 6Siodopenicillanate (0.48 g) to give the title product as an amorphous foam (490 mg).

IR 1785 cm-'.

NMR (CDCl3). 1.49 (6H,s), 1.58 (3H,s), 1.68 (3H,s), 4.48 (H,s), 4.55 (3H,s,C(3) - H + CH2O), 5.34-5.78 (4H,m), 5.89 (2H,s), 6.85-7.45 (5H,m).

Claims (3)

1. Compounds of the formula (II) as herein before defined.

2. Pharmaceutical 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.