Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1986-08-11
1988-08-02
Gersil, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
548200, C07D27706, A61K 3141
Patent
active
047613998
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to compounds having pharmaceutical activity and more particularly it concerns dipeptide compounds and their use in the preventive and curative treatment of pathologic syndromes deriving from low intracellular glutathione (GSH) levels.
The invention concerns also pharmaceutical preparations containing the dipeptides as an active ingredient.
An object of the invention are the compounds of formula ##STR3## wherein the group ##STR4## represents the residue of a natural amino acid selected from the group consisting of glycine, alanine, beta-alanine, phenylalanine, isoleucine, methionine, proline, aspartic acid and arginine; R represents a hydrogen atom or a C.sub.1 -C.sub.4 alkyl; and their acid-addition salts with pharmaceutically acceptable organic or inorganic acids.
Specific examples of the compounds of formula I are: formula ##STR5## (2-methyl-thiazolidin-4-carbonyl)-alanine and the esters thereof, of formula ##STR6## (2-methyl-thiazolidin-4-carbonyl)-beta-alanine and the esters thereof, of formula ##STR7## (2-methyl-thiazolidin-4-carbonyl)-phenylalanine and the esters thereof, of formula ##STR8## (2-methyl-thiazolidin-4-carbonyl)-isoleucine and the esters thereof, of formula ##STR9## (2-methyl-thiazolidin-4-carbonyl)-methionine and the esters thereof, of formula ##STR10## (2-methyl-thiazolidin-4-carbonyl)-proline and the esters thereof, of formula ##STR11## (2-methyl-thiazolidin-4-carbonyl)-aspartic acid and the esters thereof, of formula ##STR12## (2-methyl-thiazolidin-4-carbonyl)-arginine and the esters thereof, of formula ##STR13## and the pharmaceutically acceptable salts thereof.
In the above compounds (I-a,i), R.sub.1 is the group ##STR14## and R is a hydrogen atom or a C.sub.1 -C.sub.4 alkyl.
The preparation of the compounds of formula I are carried out by condensing 2-methyl-thiazolidine-4-carboxylic acid, suitably protected on the nitrogen atom, with an ester of the selected amino acid in the presence of a coupling agent.
A suitable protecting group is, for example, the t-butoxycarbonyl group.
A coupling agent, dicyclohexylcarbodiimide in the presence of N-hydroxy-benzotriazole may be used.
By removal of the protecting group, the esters of formula I are obtained; from these, if desired, the free acids are obtained by hydrolysis.
Alternatively the hydrolysis may precede the removal of the protecting group on nitrogen atom of the 2-methyl-thiazolidine-4-carboxylic moiety.
When the amino acid to be condensed with 2-methyl-thiazolidine-4-carboxylic acid is aspartic acid or arginine it is advisable that the second carboxy group or respectively amino group of said amino acids, be protected.
The protection and the liberation of said groups is carried out according to methods known in the chemistry of amino acids. The preparation of the acid addition salts is carried out according to usual procedures.
It is evident to the expert in the field that the compounds of formula I have asymmetric carbon atoms and thus they exist in the form of various stereoisomers.
If desired, it is possible to separate the stereoisomers according to usual procedures both as final products and as intermediates. The single isomers as well as their mixture are comprised in the scope of the present invention.
The compounds of the invention have shown to be able to promote the reconstitution of the cellular content of glutathione (GSH) and to provide an effective protection against the cellular damages caused by endogenous as well as exogenous toxic factors. GSH is, at the intracellular level, the antidote physiologically appointed to the neutralization and thus detoxication, by the formation of covalent bonds, of highly reactive toxic substances of endogenous or exogenous origin.
Depletion in GSH involves the starting of cellular degeneration and necrosis processes (Larsson et al. eds., "Function of GSH", Raven Press, N.Y., 1983).
The compounds of the invention have shown to be endowed also with positive characteristics of bioavailability and general and local tolerability.
Thus, they are useful drugs
REFERENCES:
Dubini, Chemical Abstracts, vol. 95, #1257846 (1981).
Carenzi Angelo
Della Bella Davide
Pilotto Alberto
Portelli Mario
Gersil Robert
Zambon S.p.A.
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