GB2089797A - B-Lactam Antibiotics - Google Patents

Abstract

B-Lactam antibiotics of the formula: <IMAGE> wherein R is fluoro, chloro, bromo or iodo; R<3> is a hydrogen atom or a lower alkyl, aryl or aralkyl group; R<5> is an acyl group known to broaden the spectrum of phenyl- glycylamino-penicillin antibiotics; and R<6> is a hydrogen atom or a hydroxyl or lower alkanoyloxy group; pharmaceutical compositions thereof and processes for their preparation are described.

Description

SPECIFICATION ss-Lactam antiobiotics This invention relates to sslactam antibiotics and in particular to methylene bis-esters of certain penicillins with a 6-P-halopenicillanic acid sslactamase 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-P-halopenicillanic acids of the formula:

where 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 sslactamase enzymes and are thus useful to enhance the effectiveness of penicillin and cephalosporin antibiotics against strains of bacteria which produce ss-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 is a N-substituted-phenylglycylamino-penicillin linked to the 6-ss-halo- penicillanic acid as a methylene bis-ester. Although ss-lactamase inhibitors can generally be coadministered with the antibiotic we have discovered that it is advantageous to link these molecules chemically in this way because the resulting compound has advantages in absorption from the gastrointestinal tract.In addition this enables the resulting compounds to be hydrolysed after administration 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 ss-lactamase inhibitor are thus released into circulation at the same time, and the advantageous synergystic 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 hydrogen atom or a lower alkyl, aryl or aralkyl group; R5 is an acyl group known to broaden the spectrum of phenylglycylamino-penicillin antibiotics; and R6 is a hydrogen atom or a hydroxyl or lower alkanoyloxy group.

Especially useful compounds are those wherein R is iodo and those in which R5 is a group of the formula:

The term lower alkyl as used herein means a C-I to C-S 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 cr-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 penicillin of formula:

wherein R5 and R6 are as previously defined and mX is a cation and wherein any reactive group in R5 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 ethylacetate. 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-crystallization or by chromatography.

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

wherein R3, R5, R6 and X are as previously defined, is reacted with a salt of 6-fi-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 penicillin of formula (IV) is reacted with a compound of the formula:

wherein R3 and X 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 aikalimetal halide) to give the compound of formula (it). Particularly useful in this respect are the compounds of formula (VI) wherein R4 is a trifluoromethyl group.

The compounds of formula (VI) and methods and conditions for performing the displacement reaction with halide ion are described in out co-pending U.K. Patent Application No. 8036325.

The starting materials of formula (III), (V) and (Vl) may be prepared from the corresponding salt of the 6-fi-halopenicillanic acid, penicillin or 6-P-perhalosulphonyloxy 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, 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 (Vl) 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; thus, for example, reaction with sodium iodide yields the compound of formula (III), wherein R and X are both iodo.

The penicillains 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 sslactamase inhibitor and a broad spectrum penicillin any 'biotic of value for the treatment of a variety of infectious diseases. The compounds may be adrninistered 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 proporton 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 s'~arate, 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 dosage 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 1 0 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 (cam~'). 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 1 6/'-lodopenicil!anoyloxymethyl 6fijD-2-(3-methanesulphonyl-2-oxoimidazolldine- 1 -carboxamido)- 2-phenylacetamido]penicillanate A solution of sodium 6-(D-2-[3-methanesulphonyl-2-oxoimidazolidine- 1 -carboxamido)2-pheny- lacetamido] penicillanate hydrate (150 mg) and iodomethyl 6ss-iodopenicillanate (120 mg) in N,N-dimethylformamide (5 ml) was stirred at 0.5"C for 1 hour. The solvent was diluted with ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate (10 ml) and water (4 X 50 ml). The solvent was dried (MgS04) and removed in vacuo. The residue was triturated with dry diethyl ether and filtered to afford the title compound as a white powder (150 mg).

m.p. 139-141"C.

IR 1780 cm - t NMR (CD3COCD3). 8 1.45(3H,s), 1.48(3H,s), 1.53(3H,s), 1.68(3H,s), 3.30(3H,s), 3.88(4H,s), 4.37(H,s), 4.56(H,s), 5.37-5.8(5H,m) 5.93(2H,s), 7.2-7.7(5H,m), 8.1(H,d,J = 8), 8.9(H,d,J = 7).

Example 2 6fi-lodopenicillanoyloxymethyl 6ss-[D-2-(4-ethyl-2, 3-dioxopiperazine- 1 -carboxamido)-2-phenylace- tamido] penicillanate The procedure of Example 1 was followed but using piperacillin (sodium salt) and iodomethyl 6ss-iodopenicillanate to give the title compound.

IR 1780 cm-1.

NMR CD3COCD3. 8 1.16(3H,t,J = 7), 1 .46(3H,s), 1.50(3H,s), 1.56(3H,s), 1.69(3H,s), 3,48(2H,q,J = 7), 3.6-3.8(2H,m), 3.90-4.20(2H,m), 4.37(H,s), 4.56(H,s), 5.36-5.76 (4H,m). 5.84-5.98(3H,m), 7.2-7.6(5H,m), 8.04(H,d,J = 8), 9.9(H,d,J = 8).

Example 3 6ss-lodopenicillanoyloxymethyl 6ss-[D-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-2-(4-acetoxy- phenyl)acetamido] penicillanate The procedure of Example 1 was followed but using sodium 6ss-[D-2-(4-ethyl-2,3-dioxopipera- zine-1-carboxamido)-2-(4-acetoxyphenyl) acetamido] penicillanate and iodomethyl 6ss-iodopenicil- lanate to give the title product.

IR 1780,1710 and 1680 cm-1.

NMR CD3COCD3 8 1.20 (3H,t,J = 7), 1.50(9H,br m), 1 .72(3H,s), 2.30(3H,s), 3.2-3.9(4H,br m), 3.9-4.25(2H,br m), 4.46 and 4.64 (each 1H,s,C-3 Hs), 5.4-6.1(7H,br m), 7.16(2H,d,J = 9), 7.60(2H,d,J = 9), 8.13(1 H,d,J = 7), 10.04(1H,d,J = 7).

Example 4 The procedure of Example 1 is followed but starting with the appropriate penicillin to yield the following compounds: 6 P-lodopenicillanoyloxymethyl 6 ss[D-2-(2-oxoim idazolidine- 1 -carboxamido)-2-phenylacetami- do] penicillanate; 6 8-lodopenicillanoyloxymethyl 6 ss-[D-2-(4-ethyl-2,3-dioxopiperazine-1 -carboxamido)-2-(p-hy- droxyphenyl)acetamido] penicillanate.

Claims (3)

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