Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-05-24
1998-04-07
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548537, A61K 3140, C01D20112
Patent
active
057365652
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP93/03354 filed Nov. 30, 1993.
FIELD OF THE INVENTION
The present invention is referred to sulphur-acylated derivatives of L-pyroglutamyl-L-cysteine, also denominated 2-(S)-(2-pyrrolidone-5-(S)-carbonylamido)-3-mercaptopropionic acid, which are suitable for the treatment of diseases connected with glutathione deficiency, the process for their preparation, and the pharmaceutical compositions containing same.
PRIOR ART
Glutathione, a universal component of mammals cells, plays a very important role in oxyreductive metabolic processes. In particular, glutathione--active in the reduced form (GSH)--thanks to the presence of the --SH group plays a key role in various cellular defense and repair mechanisms.
For example, GSH is a detoxicant of organic peroxides, free radicals, and endogenous and exogenous toxic agents, the latter being also denominated xenobiotic agents (Flohe L. et al., Glutathione: Metabolism and Function, Arias M. and Jacoby W. B. eds., Raven Press, New York, 115-135, 1978; Bellomo G., Richelmi P. et al., Biochem. Pharmacol., 36, 1313, 1987; Di Monte D. et al., Arch. Biochem. Biophys., 235, 343, 1984) and offers protection against potentially hepatotoxic compounds (ethyl alcohol and some groups of drugs) (Spice H., Parcher C. M., Smith G., Agent Actions, 4, 125, 1974).
At present, reduced glutathione is commercially available in various specialties utilized as detoxicants (e.g. for the treatment of intoxications induced by antineoplastic, antitubercular, neuroleptic, antidepressant drugs and by paracetamol), in the prophylaxis and treatment of damages induced by exposure to X-rays, and in the treatment of alcohol syndrome and associated disorders. Furthermore, as reported in literature (Sies H. and Cadenas E., Biological Basis of Detoxication, Caldwell J. and Jekoby B. eds., San Diego Academic, 1988), a pathological or physiological or experimental deficiency of GSH causes injuries to the involved brain regions.
Recently, evidence has pointed to a considerable involvement of GSH in the immune system of the organism, e.g. by providing cells with the cysteine required to improve their functioning.
It is, therefore, very important to have drugs that increase or restore optimal glutathione concentrations and, consequently, are suitable for the treatment of diseases like psychic fatiguing states, cognitive deficits of the evolutive age, mental deterioration in the elderly, humour disturbances, acute and chronic alcoholism, hepatic diseases following alcohol abuse and intoxication induced by some chemotherapic, antineoplastic, and antitubercular drugs.
Pharmaceutical compositions containing L-pyroglutamyl-L-cysteine, which are suitable for the treatment of cataract in humans and other mammals (Italian patent application No. 19783 A/88) and of states induced by glutathione deficiency (Italian patent application No. 21967 Reg. A) are known.
European patent application No. A2 498 268 is referred to L-pyroglutamic acid derivatives containing either C.sub.3 -C.sub.4 L-amino acids or compounds, such as for example homocysteine thiolactone, having an immunostimulating, antiradicals, antitoxic, antishock, and antiageing action.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is referred to acyl derivatives of L-pyroglutamyl-L-cysteine of formula (I) ##STR2## where R is a linear or branched alkyl containing from 1 to 6 carbon atoms, and their pharmaceutically acceptable salts.
The Applicant found that the derivatives of formula I) and the compositions containing same enhance the synthesis of endogenous GSH in vivo, thus modulating the intracellular "oxidative" state. In particular, derivatives of formula (I) were found to enhance the formation of hepatic GSH in vivo more than GSH and their single constituents (5-oxyproline and cysteine) (cf. Test 1) and to be capable of permeating cellular membranes (cf. Test 2).
Compared with GSH, derivatives of formula (I) show a better penetration into the cells and an improved bioavailability after oral administration
REFERENCES:
patent: 5254579 (1993-10-01), Poli et al.
H. Sprince, C.M. Parker, G.S. Smith, and L.J. Gonzales, "Protection Against Acetaldehyde Toxicity in the Rat by L-Cysteine, Thiamin and L-2-Methylthiazolidine-4-carboxylic acid, Agents and Actions, vol. 4/2 (1974) pp. 125-130".
M. Frankel, D. Gertner, H. Jacobson, and L. Zilkha, "Syntheses of poly-S.alkyl-L-cysteines", J. Chem. Soc., 1960, 1390-1393.
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D. DiMonte, G. Bellomo, H. Thor, P. Nicotera and S. Orrenius, "Menadione-Induced Cytotoxicity is Associated with Protein Thiol Oxidation and Alteration in Intracellular Ca.sup.+2 Homeostasis", Archives of Bioch. and Biophy., vol. 235, No. 2, Dec., pp. 343-350 (1984).
C.A.; 91:21136t; (1979), vol. 91, Inoue, et al.
Gross Laura R.
Prospa B.V.
Richter Johann
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