Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1994-11-28
1996-06-11
Dees, Jose G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
560151, 560147, A61K 31195
Patent
active
055256287
DESCRIPTION:
BRIEF SUMMARY
This application is filed under U.S.C. 371 of the application PCT/EP 93101462 filed 6/9/93.
The present invention concerns new salts of the L-.gamma.-glutamyl-L-cysteinyl alkyl esters.
More particularly, the invention relates to the salts with amino acids of glutathione (C.sub.1 -C.sub.6) alkylesters and to their solvates. The invention further relates to a process for the preparation of these new salts and to pharmaceutical compositions containing such salts as active ingredient.
Glutathione, L-.gamma.-glutamyl-L-cysteinylglycine or GSH, is represented by the formula (A) ##STR2## Glutathione, a tripeptide containing an SH group, is well known as a cellular reducer, as a catalyst in a great number of biological reactions, as a metabolic reagent, and as a form of cysteine storage and control.
Glutathione plays a very important role in cell protection against free radicals, against reactive oxygenated species such as hydroperoxides and peroxides, and against toxic compounds of either endogenous and hexogenous origin (A. Meister et al., Ann. Rev. Biochen 52,711,1983).
An increase of intracellular GSH may therefore induce cell protection against damage due to radiation, or to toxic chemical species, such as endogenous peroxides or highly toxic drugs.
Glutathione as such, however, cannot pass the cellular barrier and consequently does not enter cells, while its esters do. More particularly its ethylester (GSEt) is capable of penetrating the cells, thus undergoing in situ hydrolization (M. E. Anderson et al. Arch. Biochem. Biophys. 1985,239,538-538; U.S. Pat. No. 170,489).
Glutathione ethylester (on glycine) is prepared according to the method described in the publication by M. E. Anderson et al. mentioned above, but the final product always contains a certain amount of diester (on both glutamic acid and glycine) which must be eliminated as it is toxic.
This impurity can be removed by chromatography on weak cation exchange resin columns, as described in U.S. Pat. 4,710,489, but such an operation is not easy, when it has to be performed on an industrial scale.
U.S. Pat. No. 4,709,013 describes glutathione ester sulphates highly crystallizable and therefore easily purifiable, allowing their easy transformation into glutathione monoester devoid of the toxic diester.
Although the sulphates described in the above document are crystallizable, the thus obtained crystals are hygroscopic. The usefulness of such sulphates is therefore limited to their use as intermediates in the purification of glutathione esters.
Consequently, these sulphates cannot be used as active ingredients of pharmaceutical compositions, due to the difficulties encountered in their handling in pharmaceutical technique.
Another reason which hinders said sulphates from being used as medicaments is their high acidity.
Patent EP 257 992 describes the use of glutathione monoesters for the preparation of agents suitable for use in the prophylaxis and treatment of cerebral ischemia and, as active ingredients, it reports also inorganic salts such as hydrochlorides, nitrates, or organic ones such as oxalates, p-toluensulphonates, maleates, etc. In the above document it is however pointed out that when such monoesters are being administered in the form of salts, they are previously desalted, or administered by concurrent addition of a base, i.e. sodium carbonate, neutralizing them. Consequently, glutathione esters stable crystalline salts directly useful as active ingredients for pharmaceutical compositions are not known in literature.
It has now surprisingly been found that glutathione monoalkylesters, namely the esters of a tripeptide with an initial alpha-aminoacid unit, easily yield salts with other aminoacids.
Moreover, it has been found that these salts with aminoacids are crystalline and not hygroscopic.
Finally, it has been found that the above reported crystalline non hygroscopic salts of glutathione alkylesters are even pharmacologically more active that the free base, and are easy to handle in pharmaceutical technique for the preparation of compos
Fregnan Giancarlo B.
Inglesi Marco
Nicola Massimo
Vandoni Guido
Barts Samuel
Dees Jos,e G.
Edmond Pharma S.r.l.
Meller Michael N.
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