Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-12-03
1998-07-28
McKane, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540349, A61K 31395, C07D20512
Patent
active
057863512
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This application is a 371 of PCT/GB95/03039 filed Dec. 22, 1995.
The present invention relates to clavulanic acid salts, their preparation and pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
Clavulanic acid is active in antibiotic formulations because it inhibits many of the beta-lactamase enzymes, which cleave the beta-lactam ring of anti-microbial agents such as penicillins and cephalosporins. Clavulanic acid therefore improves the antibacterial actions of these antimicrobial agents. Clavulanic acid has the following formula: ##STR2##
GB-A-1578739 discloses a class of amine salts of clavulanic acid, and a process for the preparation of clavulanic acid, in which the salts may be more easily formulated to give stable pharmaceutical compositions than previously described salts of clavulanic acid. Other amine salts of clavulanic acid are disclosed in, for example, GB-A-2264944; WO 93/25557 and WO 94/22873; and EP-A-0026044, EP-A-0387178 and EP-A-0562583.
Typically, such amine salts of clavulanic acid either do not crystallise or require the addition of very large amounts of a solvent, such as acetone, in order to cause crystallisation, or crystallisation in the form of fine needle shaped crystals which do not settle readily and are difficult to filter, wash and dry.
Accordingly, it is the purpose of the present invention to alleviate such difficulties, and to provide a highly stable pure salt of clavulanic acid which can be easily crystallised, or crystallise in the form of rosette shaped crystals which are easy to filter.
SUMMARY OF THE INVENTION
Thus, according to one aspect of the present invention, there is provided a di-clavulanate salt derived from clavulanic acid and a diamino ether of the formula ##STR3## where R.sup.1 is an alkylene group (the term alkylene encompassing cycloalkylene and alkyl substituted cycloalkylene), optionally having one or more inert substituents; and each of R.sup.2 and R.sup.3 is a hydrogen atom or an alkyl group (the term alkyl encompassing cycloalkyl and alkyl substituted cycloalkyl), optionally having one or more inert substituents, or R.sup.2 and R.sup.3 together complete a heterocyclic ring having 4 to 7 carbon atoms, again optionally having one or more inert substituents. When R.sup.2 and R.sup.3 represent alkyl groups, they each preferably have no more than 8 carbon atoms; they are preferably both the same.
It is preferred that R.sup.1 contains no more than four carbon atoms, and that the R.sup.2 and R.sup.3 groups together contain no more than four carbon atoms. Most preferably, the diamino ether comprises bis (2-dimethylaminoethyl) ether, which advantageously forms a highly pure salt of clavulanic acid and which can be crystallised from aqueous solution by the addition of a suitable solvent such as acetone or iso-propanol. It has been found that using bis (2-dimethylaminoethyl) ether, no crystalline mono clavulanate salt can be isolated, which advantageously allows a substantially homogeneous di-clavulanate to be isolated. Furthermore, the di-clavulanate salt of bis (2-methylaminoethyl) ether does not normally form a distinct solvate; this characteristic prevents any carry over of solvent, thus substantially avoiding contamination of any subsequent processing stages.
The salts according to the invention are themselves pharmaceutically acceptable and may therefore be used together with a carrier, diluent or excipient, in a pharmaceutical formulation. Alternatively, the salts may be used as intermediates for the preparation of further pharmaceutically acceptable salts of clavulanic acid, such as the potassium salt, and for pharmaceutical compositions containing such a salt.
There is further provided a process for preparing a diamino ether salt of clavulanic acid as defined above, which comprises reacting a diamino ether with clavulanic acid in an organic solvent, and isolating the resulting salt. Preferably, the organic solvent comprises an aliphatic carboxylic ester or a substantially water-immiscible aliphatic ketone;
REFERENCES:
patent: 4144242 (1979-03-01), Fleming et al.
patent: 4255332 (1981-03-01), Davies
patent: 4454069 (1984-06-01), Cook et al.
McKane Joseph
Spurcourt Limited
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