Partially modified and retro-inverted tetrapeptides analogues of

Details Partially modified and retro-inverted tetrapeptides analogues of Partially modified and retro-inverted tetrapeptides analogues of

1994-09-27

1996-05-28

Nucker, Christine M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

530330, A61K 3807, C07K 502

Patent

active

055211593

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to retro-inverted tetrapeptides analogues of C-reactive protein fragments (hereinafter CRP).
CRP is a protein generally having very low blood concentration, which rises up to two thousand times following inflammatory process [J. J. Morley and I. Kushner, Am. N.Y. Acad. Sci., 389, 406-418 (1989)]. F. A. Robey et al , J. Biol. Chem., 262 No.15 7053-7057 (1987) disclose three CRP tetrapeptide sequences very similar to the ones of tuftsin. The chemically sinthetised tetrapeptides show to stimulate the phagocytic leukocytes, to produce superoxide and to induce mononuclear cells to produce interleukin 1, in a qualitatively and quantitatively tuftsin-like manner. Like tuftsin, the three CRP tetrapeptides should be rapidly in vivo metabolised by proteases, and yield peptide metabolites which could competitively inhibit the biological activity/ies of the parent peptides. It has been now surprisingly found that partially modified and N-terminal retro-inverted analogues of said CRP tetrapeptide fragments show not only a considerable stability against the enzymatic degradation while maintaining the immunomodulating activity already seen for tuftsin (see EP-A-0 253 190), but in particular they are able to determine different biological effects depending on the structure and the dose used, specifically in the treatment of septic shock. Therefore the present invention relates to retro-inverted tetrapeptides of the general formula I ##STR2## wherein R is a hydrogen atom or the side-chain of threonine; R.sub.1 is the side-chain of arginine, leucine or glutamine; and R.sub.2 is a hydrogen atom or a metabolically perishable acyl group; with the proviso that when R.sub.1 is the side-chain of arginine, R cannot be the side-chain of threonine; and their diastereoisomeric forms and pharmacologically acceptable salts, esters and amides.
Particularly, the invention relates to the retro-inverted tetrapeptides gGly-(R,S)mLys-Pro-Arg, gThr-(R,S)mLys-Pro-Leu, gThr-(R,S)mLys-Pro-Gln, wherein the prefixes g and m mean that the aminoacid is, respectively, a gem-diamine and malonyl residue, and the diastereoisomeric forms thereof.
The retro-inverted tetrapeptides of the present invention are synthetised in accordance with known methods, which the skilled in the art may choose depending on the kind of aminoacids to retroinvert.
For example, when the gem-diamine residue is the 1,1-diaminomethane group (gGly), the retro-inverted tetrapeptide may be prepared by first reacting the Meldrum's acid derivative c-mLys(Z) (i.e. 5-[4-benzyloxycarbonyl]-2,2-dimethyl-1,3-dioxane-4,6-dione) with H-Gly-NH.sub.2 in the presence of a sylanising agent such as N,O-bis(trimethylsylyl)acetamide (TSMAc), trimethylsylylchloride (TMS-Cl) or trimethylsylylcianide (TMSCN) (M.J.O. Anteunis & Char. Becu, Bull. Soc. Chim. Belg., 96, 119-139 1986). The second group on the malonyl residue of the pseudopeptide OH-(R,S)mLys(Z)-Gly-NH.sub.2 (Z=benzyloxycarbonyl) thus obtained is condensed with t-butyl prolinate in the presence of dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) to give the pseudotripeptide [(R,S)mLys(Z)-Gly-NH.sub.2 ]-Pro-H. Its proline carboxy group is activated with DCC and N-hydroxy-succinimide (HOSu) and reacted with unprotected arginine [Gottlieb, P. et al., Ann. N.Y. Acad. Sci., 419, 12 (1983 )] to obtain the retro-inverted tetrapeptide [(R,S)mLys(Z)-Gly-NH.sub.2 ]-Pro-Arg-OH. The purification is then effected through RP-DC deplacement chromatography, and by this way it is also possible to yield the separation of diastereoisomers, if desired. The purified product is catalytically hydrogenated by HCOOH in the presence of palladium, to remove the remaining protective groups, and then treated with [I,I-bis(trifluoroacetoxy)-iodo]benzene (TIB) for turning the glycine carboxamide into the N-terminal residue of gGly. One last purification by ion exchange chromatography enable to obtain the final product as acetate.
Another example is where threonine is the gem-diamine residue. The synthesis of the retro-inverte

REFERENCES:
patent: 4816560 (1989-03-01), Verdini et al.
Biotechnology Newswatch, Aug. 1, 1994, p. 1 and 4.
The Washington Post, Jan. 19, 1993, p. D3.
Cross, A. et al. (1993) Choice of bacteria in animal models of sepsis. Infection and Immunity 61, 2741-2747. See entire article.

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